Norman^9,12,13 used the uMMA test to screen senior residence (over age 65) (N = 68) independently living in a retirement apartment and reported 12% with elevated uMMA (normal uMMA < 5.0) and 7% with uMMA levels above 7 and below normal serum B12 levels. Using today's normal standard for uMMA of (< 3.8) at least 22% of the subjects showed metabolic deficiency. Reporting the high prevalence of B12 deficiency in seniors coupled with the high incidence neurologic disease in nonanemic B12 deficient individuals alerted researchers and the public to the B12 deficiency epidemic. These findings were spotlighted in both the Cincinnati, OH and national press to inform physicians and the public to the dangers of undetected B12 deficiency. An editorial in the Cincinnati Enquirer, August 19, 1985, notes

"Some aged patients with problems of vision, memory loss, paranoia and perhaps dementia have been erroneously diagnosed as having AD when they were suffering from vitamin B12 deficiency."

     Similarly, from 1987 to 1992, The Vitamin B12 Report was mailed to Cincinnati physicians and selected national doctors, hospitals, and clinics.⁴⁵ Subsequently, Norman and Morrison¹⁴ identified 7 % of 809 elderly individuals as vitamin B12 deficient with high uMMA (normal < 4.0). The lower prevalence of vitamin B12 deficiency identified in this later study may be attributed to increased physician/public awareness of B12 deficient individuals without anemia, different study populations, and increased consumption of multivitamins and/or B12 fortified cereals.

     It has been estimated, depending upon the population, that from 5% to 15% of elderly individuals will have vitamin B12 deficiency.²⁸ Of persons age 60, up to 30% have atrophic gastritis. Over age 70, up to 50% have atrophic gastritis.⁴⁶ Atrophic gastritis contributes to vitamin B12 deficiency but does not affect the absorption of crystalline B12.⁴⁷ Therefore, the Food and Nutrition Board has recommended that the RDA for vitamin B12 for adults of all ages be increased to 2.4 micrograms from the 1989 RDA of 2.0 and advised that elderly people consume vitamin B12 fortified foods (e.g. cereals) and/or vitamin B12 supplements.⁴⁷

     Strict vegetarians are at particular risk for developing B12 deficiency within two years.⁵ Serious neurologic deterioration may occur in infants that develop B12 deficiency through a nursing mother on a strict vegetarian diet or a mother with untreated pernicious anemia. Persistent B12 deficiency^47A and long-term neurologic consequences can occur from a B12 deficient diet early in life.^47B

     Mild B12 deficiency in older Dutch individuals could be attributed to inadequate B12 intake or atrophic gastritis in only 28% of the population and those taking supplements (7.8 micrograms per day) had similar SMMA levels as those not taking supplements.¹ Stabler et. al.⁴⁸ found that multivitamin supplementation (6 micrograms of B12) was not associated with lower SMMA levels in their study population. However, SMMA levels were lower in the group taking > 9 micrograms B12 daily and particularly in the cohort consuming 33-1000 micrograms. Howard et. al.⁴⁹ found that mild B12 deficiency in their elderly study population was not associated with poor B12 diet intake. Only 1.7% (3/173) ingested < 2 micrograms B12 per day and one of the three had normal B12 status. Eighty of 173 (46.2%) subjects took multivitamin or B12 supplements but did not have lower SMMA levels than nonusers. Sixty-nine subjects (39.9%) ingested < 6 micrograms B12 daily but did have suffer greater B12 deficiency than those consuming > 6 micrograms. They did not specify the prevalence of B12 deficiency in this population but did note that the decrease prevalence may be related to B12 supplement use. B12 supplement use may reduce but will not eliminate B12 deficiency in the elderly.^1,2,48,49 Carmel et al. report the use of B12 supplements will reduce the prevalence of B12 deficiency in elderly population by only half.^1,2,49

     However, Norkus et al.^49A found no effect between multivitamin (MVT) use (2-30 micrograms B12 daily) and B12 status in elderly subjects suggesting bioavailability of B12 from MVT use can be unpredictable.^4A Crane et al. recommend subjects in their studies chew 500 microgram B12 tablets since some do not dissolve quickly enough to obtain consistent results.^49B,20 Kondo et al.^49C report vitamin-mineral preparations containing iron and copper may convert B12 into anti-B12. Tucker et al.^D49 found that the use of supplements, fortified cereals, and milk had a protective effect reducing the prevalence of B12 deficiency. Although they did not assess metabolic B12 deficiency they found in their study of 2999 subjects ages 26 to 83 supplement users were significantly less likely than non-supplement users to have B12 concentrations less than 185 pmole/L (250 pg/ml), 8% versus 20%, respectively. The usual dose in a MVT was 6 micrograms B12 and individuals consuming 10-30 micrograms B12 did not have significantly lower plasma B12 concentrations. A survey in UK found 5% with B12 concentrations below 200 pg/ml in all ages between 18 to 64 with no increase in age.^49E Norman and Morrison¹⁴ in their study found no statistically significant association between age and uMMA levels, but levels were higher in females, p< .02.

     NCL does not recommend taking a large excess of vitamin B12 without first being diagnosed as B12 deficient and then advised by physician. For example, information for use of an FDA approved nasal gel B12 product cautions:

1. "Patients with early Leber's disease (hereditary optic nerve atrophy) who were treated with vitamin B12 suffered severe and swift optic atrophy. 2. Hypokalemia and sudden death may occur in severe megaloblastic anemia which is treated intensely with vitamin B12. Folic acid is not a substitute for vitamin B12 although it may improve B12-dependent megaloblastic anemia. Exclusive use of folic acid in treating B12-deficient megaloblastic anemia could result in progressive and irreversible neurologic damage. 3. Anaphylactic shock and death have been reported after parenteral vitamin B12 administration. No such reactions have been reported in clinical trials with the nasal gel."

     B12 toxicity is rare; however, the USA Food and Nutrition Board, National Academy of Sciences (2001) has not established a maximum safe level of B12 and advises caution may be warranted in consuming levels above recommended intakes. The Recommended Dietary Allowance (RDA) for adults is 2.4 micrograms/day and those older than 50 should consume foods (i.e. cereals) fortified with B12 or a vitamin B12 supplement.⁴⁷ The medium intake of vitamin B12 from food in the United States was estimated to be approximetly 5 micrograms/day for men and 3.5 micrograms/day for women. B12 absorption estimates from microgram doses are: 50% for 1, 20% for 5, 5% for 25, 1% for 500, and .05% for 500 micrograms B12 with food in individuals with normal gastric function.⁴⁷

     To illustrate the physician's confusion in establishing a diagnosis for vitamin B12 deficiency, the criteria used in four recent studies are reviewed.

Reference 1: excluded subjects with renal insufficiency (RI), low to low normal serum B12 (< 260 pmoles/L) and high SMMA (> 320 n moles/L).

Reference 49: exclude RI, low serum B12 (< 140), high SMMA (> 376), and high Hcys (> 16.8 micromole/L).

Reference 2: exclude RI, serum B12 < 140, SMMA > 376, serum Hcys but B12 diagnosis criteria was not defined.

Reference 48 defines categories: 1. high cutoff: serum B12 < 258 and SMMA > 271 and MMA greater than methylcitric acid (MCA) concentration. 2. low cutoff: serum B12 < 148 and SMMA > 271 and SMMA > MCA. 3. B12 deficiency with possible folate deficiency: Subjects above with high SMMA and Hcys > 13.9 but serum folate < 11.4 nmoles/L.4 RI with elevated SMMA and Hcys was defined as not caused by B12 deficiency with serum creatinine > 271 micromoles/L and one of the following: SMMA > 271, Hcy > 13.9, cystathiuoinine > 342 or MCA > 228.

     According to the papers cited in this review, all of the above tests are not needed, since the diagnosis of vitamin B12 deficiency can be reliably established with the uMMA test using a single spot urine specimen.¹⁴ The uMMA test value is normalized to urine creatinine levels so RI is not a concern. As mention previously, Hcys levels are not required when using the uMMA test. The uMMA test in a recent review of diagnostic tests for detecting B12 deficiency was given the highest classification for diagnostic utility.⁵⁰ The criticism of the uMMA test such as the measurement of uMMA is cumbersome compared with measurement in serum is unjustified. In actuality, since MMA is 40 times more concentrated in urine than serum, it is easier to measure.²¹ The measurement of urine creatinine contributes to the high accuracy of the uMMA test since unlike SMMA it is normalized to creatinine.²¹ Another criticism is that uMMA is more influenced than SMMA by food intake. This opinion was based on studies with only three individuals, and uMMA levels remained in the normal range below 2.5 micrograms MMA per milligram creatinine (normal < 3.8), even when the MMA metabolic pathway was stress tested with a high protein meal.⁴⁴ As reported herein, thousands of subjects tested using uMMA show no problem with falsely high uMMA. Conversely, falsely high SMMA levels are a major liability limiting the usefulness of that test.

     The Hcys test may have value in establishing the diagnosis of folate deficiency but is not needed in addition to uMMA assay for detecting B12 deficiency as previously documented. In addition, folate deficiency is less common since the FDA mandated beginning in January 1998 all enriched cereal grains be fortified with 140 micrograms folic acid per 100 grams of grain. This strategy has worked well by decreasing the USA prevalence of neural tube defects by 19%^51,52 and now Americans are showing folic acid levels literally off the measurement scale.⁵² Since folate can also reduce Hcys levels, a risk factor for cardiovascular disease, numerous studies are underway to determine if folate supplements will also reduce the risk of cardiovascular disease. uMMA levels are more sensitive for identifying B12 deficiency than Hcys and may be beneficial in identifying normal levels of Hcys that could be reduced with B12 therapy.²⁰

     The uMMA test is the ideal screening assay for older populations. A satisfactory screening test must be specific, sensitive, reproducible, and acceptable to the population being screened. Furthermore, early diagnosis and treatment should alter the course of the disease. In addition, the prevalence of the disease in the screened population must be sufficiently high as to make the test financially justified.⁹ The uMMA test fits these criteria.^5,9,14