- B12 Functions
- Homocysteine Clearance
- Anemia, DNA, and Folate
- Lack of Anemia Does Not Mean B12 Status Is Healthy
- Methylmalonic Acid (MMA)
- Used by the enzyme methionine synthase to turn homocysteine into methionine. Methionine is further converted to the important methyl donor, S-adenosylmethionine (SAM, aka SAMe)
- Used by the enzyme methylmalonyl-CoA mutase to convert methylmalonyl-CoA to succinyl-CoA
Methionine is an essential amino acid provided by the diet. Some methionine is turned into homocysteine and without adequate vitamin B12, homocysteine builds up in the blood. Although it’s not clearly a causative factor, elevated homocysteine is associated with early death, cardiovascular disease, and dementia. For more information, see Homocysteine and Mild B12 Deficiency in Vegans.
Anemia, DNA, and Folate
Traditionally, B12 deficiency, normally resulting from the inablity to absorb B12, was diagnosed by finding abnormally large red blood cells. This sort of anemia has two names:
- Macrocytic anemia – above normal mean corpuscular volume (MCV)
- Megaloblastic anemia – abnormally large red blood cells observed under a microscope
The vitamin folate (aka folic acid) affects the anemia symptoms of B12 deficiency. Folate is needed to turn uracil into thymidine, an essential building block of DNA (4). DNA is needed for new red blood cell production and division. B12 is involved in this process because in creating methylcobalamin (used in the homocysteine to methionine reaction), B12 produces a form of folate needed to make DNA. If there is no B12 available, this form of folate can become depleted (known as the methyl-folate trap) and DNA production slows (5). See the pathway below.
Only RNA is needed to produce the hemoglobin found in the red blood cells. Unlike DNA, RNA does not require thymidine. Therefore, if there is not adequate folate, the new red blood cells (which start out as large cells called reticulocytes) divide slowly, as they are dependent on DNA for dividing. At the same time, their hemoglobin is only dependent on RNA and it is produced at a normal rate. This causes large red blood cells known as macrocytes (4, 6). If enough of these macrocytes accumulate, the result is macrocytic anemia.
If there are large amounts of incoming folate from the diet, the body does not need to rely on the regeneration of folate from the B12 cycle. Instead, it can use the extra dietary folate to produce DNA, thus preventing macrocytic anemia (see the bottom right-hand portion of Figure 1 above). This is why high intakes of folate are said to “mask” a B12 deficiency.
To complicate things further, an iron deficiency results in small red blood cells from inadequate hemoglobin synthesis and can counteract abnormally large red blood cells making it appear as though blood cell size is normal when there are multiple nutritional deficiencies (7).
Intestinal cells are also rapidly dying and being replaced using DNA. A B12 deficiency can make itself worse because it can prevent the production of the intestinal cells needed to absorb B12.
Lack of Anemia Does Not Mean B12 Status Is Healthy
Traditionally, the existence of macrocytic anemia was relied on to indicate a B12 deficiency. However, neurological disorders due to B12 deficiency commonly occur in the absence of a macrocytic anemia.
Lindenbaum et al. (8) (1988, USA) examined 141 cases of neurological problems due to B12 deficiency. 40 (28%) had no macrocytic anemia (iron deficiency may have contributed to a lack in 6 patients, and folate therapy could account for 2 others). These 40 had very high serum MMA levels (range: .76-187 µmol/l, 78% > 2 µmol/l) and homocysteine levels (23-289 µmol/l, 45% > 100 µmol/l). Characteristic features of patients with B12 deficiency but without macrocytic anemia included: sensory loss, inability to move muscles smoothly (ataxia), dementia, and psychiatric disorders. They also had borderline (and sometimes normal) B12 levels (see Table 1). One patient died during the first week of treatment, but the other 39 benefited from B12 therapy. Some patients had residual abnormalities after years of treatment.
|Table 1. B12 Levels in Neurological Patients Without Macrocytic Anemia (pg/ml)|
|Number of Patients||Serum B12|
In a 2011 study from Korea, among 35 patients with vitamin B12 deficiency, most of whom had neurological symptoms, none had anemia (12).
Methylmalonic Acid (MMA)
The second coenzyme form of B12, adenosylcobalamin, takes part in the conversion of methylmalonyl-CoA to succinyl-CoA. When B12 is not available, methylmalonyl-CoA levels increase. Methylmalonyl-CoA is then converted to methylmalonic acid (MMA) which then accumulates in the blood and urine. Since B12 is the only coenzyme required in this pathway, MMA levels are the best indicators of a B12 deficiency.
For more information on elevated methylmalonic acid, see Minimizing Methylmalonic Acid Levels.
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