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Vitamin B 12 Deficiency in Older People: Improving Diagnosis and Preventing Disability

1998; Wiley; Volume: 46; Issue: 10 Linguagem: Inglês

10.1111/j.1532-5415.1998.tb04554.x

1532-5415

Sally P. Stabler,

Metabolism and Genetic Disorders

It is fully established that the prevalence of vitamin B12 deficiency increases as people age.1, 2 This has been documented by both low serum vitamin B12 levels and, more recently, by demonstrating elevated concentrations of two vitamin B12-dependent metabolites, methylmalonic acid and total homocysteine, in the serum of these older subjects.3–5 Vitamin B12 is necessary for the clearance of homocysteine and the precursors to methylmalonic acid; thus, these compounds increase when B12 is deficient. The elevated metabolite concentrations decrease readily when vitamin B12 is administered.3, 5 The spectrum of deficiency ranges from mild abnormalities to severe metabolic B12 deficiency, with methylmalonic acid concentrations reaching the range of values found in patients with pernicious anemia who have megaloblastic anemia or spinal cord demyelination as a result of B12 deficiency.1, 6 Some of these older people have bonafide pernicious anemia (1.9% of persons older than age 65),7 but most are thought to have malabsorption of protein-bound vitamin B12.2 The natural history of patients with protein-bound B12 malabsorption is not known, especially because these individuals may absorb crystalline B12, which is found in small amounts in vitamin supplements and supplemented foods. In January 1998, folic acid was added to enriched grain products, possibly delaying the diagnosis of vitamin B12 deficiency by masking anemia and exposing untreated B12-deficient patients. The primary clinical problem at the present time is that 10 to 20% of the 50 million older adults in the United States have metabolic and/or clinical evidence of vitamin B12 deficiency and are also now consuming an extra 100 to 300 μg of folic acid, and we have no clear answers about the consequences of B12 deficiency or the benefits of diagnosis and treatment for these people. The investigation by Dr. Bernard and colleagues published in this issue8 attempts to provide information about whether this high underlying prevalence of B12 deficiency has a deleterious effect on the health of older adults. After studying 303 ambulatory older veterans, the authors concluded that vitamin B12 deficiency was associated only with "bodily pain" on the Rand 36-Item Health Survey and with a lower score on the Folstein Mini-Mental State Examination. These findings were significant if they defined B12 deficiency by a low serum B12 level (<190 pg/mL) but not when they lumped the subjects with the low B12 levels with those with B12 levels between 190 and 300 pg/mL and an associated elevated methylmalonic acid or total homocysteine value.8 What would be the benefits of diagnosing vitamin B12 deficiency in our older population= The underlying goal is to find a treatable condition and relieve suffering or to prevent future disability that would occur if the condition is not treated. We have approximately 100 years of clinical data indicating that persons with pernicious anemia have an inevitable progression of clinical abnormalities caused by B12 deficiency that were ultimately fatal in the decades before the development of treatment. Can this data be extrapolated to older people with milder malabsorption of protein-bound B12= We can use the clinical observations of pernicious anemia and clinical B12 deficiency in order to determine the possible deleterious effects of B12 deficiency on populations with other forms of deficiency. The first described clinical lesion in B12 deficiency was megaloblastic anemia, and the autoimmune disease caused by the lack of gastric secretion of intrinsic factor was thus termed pernicious anemia, even though as many as one-third of the patients may not manifest megaloblastic anemia.6 Patients with B12 deficiency are usually diagnosed with less severe megaloblastic anemia in current clinical practice. The hematocrit was severely depressed (<30%) in only 20% of a group of 86 patients who had a documented clinical response to vitamin B12 treatment as well as elevated methylmalonic acid and/or total homocysteine levels that fell with treatment.9 Anemia has been mild despite marked elevations of methylmalonic acid and/or total homocysteine in B12-deficient older people discovered in screening studies.1, 3, 4 Because most mildly anemic subjects are not symptomatic, it is possible that the survey instrument used for assessing the vitamin B12-deficient subjects in the investigation by Bernard et al. may not have been sensitive enough to detect a health affect of mild anemia. Complete blood counts were not reported for the subjects in this investigation.8 The recent increase in dietary folic acid may mask megaloblastic anemia in these B12 deficient older persons and contribute to this diagnostic problem. See also p 1199 B12-deficient megaloblastic anemia corrects completely with B12 therapy. Unfortunately, B12 deficiency also causes a demyelination of the dorsal and lateral columns of the spinal cord and peripheral nerves, with occasional lesions of the cranial nerves and cerebral white matter. Permanent disability will result if treatment is delayed.10 We can review the findings in the largest, recent series of well documented B12 deficient patients (153 episodes) with neurologic disease10 in order to determine what we can expect to find in older people with B12 deficiency. Because the mean age was 61 years in this large series, with 50% of the patients between 60 and 80 years of age, the patients are comparable to those described in Bernard et al.8 The patients with neurologic abnormalities represented 38% of all of the cases of B12 deficiency. The most common symptom (70%) was that of paresthesias, which was described as a tingling "pins and needles" sensation with burning, prickling and numbness.10 It is interesting that the investigation by Bernard et al. found that bodily pain was greater in subjects with low vitamin B12 levels. The reader will have to decide whether a question about bodily pain would uncover paresthesias, the most common symptom of B12-deficient neurologic disease. Cerebral symptoms were present in 18 (12%) of the subjects from the above described series who had B12-deficient neurologic disease.10 Eight of these 18 patients had a global dementia described as recent memory loss with mildly reduced attention span, and all but one with mental symptoms had other signs and symptoms of myelopathy or neuropathy. Other investigations have shown that memory loss and/or cognition measured with various instruments is very resistant to improvement with vitamin B12 treatment,1, 3, 9–12 even though these same individuals may have had improvements in serum metabolites, megaloblastic anemia, or myelopathy/peripheral neuropathy, and in one study these improvements were documented by electrophysiologic testing.11 Several reports show that patients who meet the criteria for Alzheimer's disease often have low vitamin B12 levels.11–14 It seems likely that many of the older patients with dementia in these series have both vitamin B12 deficiency and a primary dementing disorder such as Alzheimer's disease. Did the investigation by Bernard et al.8 simply detect those with Alzheimer's disease or other dementias who also had a low B12 level= There was not an apparent relationship between bodily pain (hopefully a measure of paresthesias) and the cognitive score, which would be expected if those abnormalities were actually related to vitamin B12 deficiency.10 Another issue discussed by Bernard et al.8 is how to diagnose clinical vitamin B12 deficiency. The definitions of deficiency used in their investigation have limited utility because there are many false-positive low B12 levels. Past investigations3, 6, 9 have shown that virtually every subject with clinical vitamin B12 deficiency who will have an objective documented response to therapy has elevated serum methylmalonic acid, frequently accompanied by elevated total homocysteine. There is a positive correlation between the serum metabolites and the severity of neurologic disease or megaloblastic anemia.6 Most clinically deficient subjects have concentrations of methylmalonic acid greater than 500 nmol/ L.6 The methylmalonic acid concentration is the most sensitive indicator of vitamin B12 status and rises in subjects with pernicious anemia15 who are treated infrequently or are receiving inadequate dosing.16 The serum B12 level lacks specificity in the range of 100 to 400 pg/mL, with approximately 50% of older adults with values in this range having associated elevated methylmalonic acid and/or homocysteine.2, 3 Even a modest degree of renal insufficiency can increase total homocysteine and methylmalonic acid (usually less than 1000 nmol/L), and this can complicate the diagnosis, particularly in the older population.1, 4, 17 If Bernard et al.8 had analyzed their clinical findings using the methylmalonic acid concentration as the marker of vitamin B12 deficiency, it is likely that false-positive low B12 values would have been seen in up to 50% of their subjects. If the subjects with low vitamin B12 and normal methylmalonic acid also happened to be those with Alzheimer's disease and a low score on the Folstein Mini-Mental Exam, then the authors' conclusion that there was a relationship between a low B12 level and poor cognition would be clinically irrelevant because such patients will not respond to vitamin B12 treatment. We can determine the number of subjects expected to have a disorder of cognition or other cerebral symptoms from B12 deficiency in this cohort by extrapolating from Healton's large series10 in which only 5% of the total of 389 episodes of B12 deficiency were accompanied by these symptoms. Therefore, only one to three of the 49 subjects found in the investigation by Bernard et al. would be likely to have cerebral systems attributable to vitamin B12 deficiency. However, the benefit of treatment for these few subjects whose cerebral symptoms would respond to vitamin B12 is enormous because few of the other disorders have specific treatment. The clinician must decide whether to treat approximately 10% of the entire older population, based on low vitamin B12 levels, or to select for treatment those with elevated methylmalonic acid, a marker of impaired B12-dependent metabolism. High serum concentrations of total homocysteine (hy-perhomocysteinemia) appear to be a risk factor for vascular disease18 and were shown recently to be a risk factor for mortality in patients with established coronary atherosclerosis.19 Hyperhomocysteinemia is frequently related to vitamin B12 deficiency in older subjects1, 20 and will often respond to vitamin B12 therapy in combination with folic acid.3, 5 Diagnosing and treating vitamin B12 deficiency in older adults may prevent complications of hyperhomocysteinemia. The investigation reported in this journal found that the use of multivitamins decreased the prevalence of the low vitamin B12 levels although the authors did not report whether serum methylmalonic acid or homocysteine concentrations were decreased.8 Previous studies have shown that the doses of vitamin B12 in most multivitamin preparations will improve B12 status4, 21 but will not eliminate cases of vitamin B12 deficiency.21 Up to 1 % of an oral dose of B12 can be absorbed, even with complete malabsorption of B12 as seen in pernicious anemia. Thus, there is interest in the required oral dose of B12 that could be used to treat the large number of vitamin B12-deficient older adults. A large oral dose (2000 μg) of vitamin B12 was as effective (probably better) as a standard intramuscular injection protocol in subjects with clinical B12 deficiency in a recent investigation.16 The issues of patient acceptance, compliance, dose, cost, and monitoring comparing oral and parenteral B12 therapy need to be investigated. In summary, vitamin B12 deficiency is extremely common in older people and may not pose a severe clinical problem for most of the affected patients. However, a small fraction may have a spectacular response to treatment because vitamin B12 deficiency remains one of the only curable causes of bone marrow failure, myelopathy/neuropathy, and cognitive disorders. It seems reasonable to improve specificity of diagnosis as well as the availability of easily administered replacement therapy.