Computación Síncrona

B

Examination of the folate pathway described in

Figure 9.1 shows that the folate cofactors in

their reduced forms are necessary for purine and pyrimidine biosynthesis. Thus, the so-called carbon one folate derivatives of 10-formyl and 5,10-methylenetetrahydrofolate (MTHF) donate respectively in the former instance the carbon 2 and the carbon 8 of the purine ring. The latter folate, 5,10-methylene THF, is a cofactor for the very important enzyme, thymidylate synthase, and is responsible for the conversion of the uracil type base found in RNA to the thymine type base which is characteristic of DNA (Figure 9.1). It can thus be anticipated that the folate deficiency or even reduced folate status will diminish and com- promise a cell’s ability to synthesize purines and pyrimidines and thus DNA. This would reduce the ability of any cell to divide appropriately but

113 Nutritional anemia: B-vitamins

would be most obvious clinically in the rapidly dividing cells of the bone marrow, which causes an anemia. It also causes a reduction in the white cells, platelets, etc. Such reduced ability to make DNA at the appropriate rate during the maturation of red cells in the bone marrow causes a less than normal number of cell divisions ingoing from the pluripotent stem cell to the erythrocytes. As red cells divide in the bone marrow compartment, the resultant two daughter cells after each division are slightly smaller than the parent cell. The reduction in the number of such divisions results in the eventual erythrocytes being larger than usual, or macrocytic, with a raised mean corpus- cular volume (MCV). Of course, the overall reduction in cell division would also result in a reduction in hemoglobin biosynthesis and also be reflected as an anemia seen in a Full Blood Count (FBC). The reduced rate of cell division results in nuclei that are larger and more poorly differenti- ated than normal. Such megaloblasts are diagnos- tic of folate deficiency anemia. What is also clear is that an identical megaloblastic anemia occurs in vitamin B12deficiency. It is identical in every

respect morphologically to that seen in folate deficiency and there is a similar rise in MCV. The biochemical explanation for this is set out in the methyl trap hypothesis (4). There are only two vitamin B12dependent enzymes in man. One of

them, methionine synthase, uses the folate cofac- tor 5 methyl THF and is part of the methylation cycle (Figure 9.1). The enzyme that synthesizes 5 methyl THF, namely 5,10-methyltenetrahydro- folate reductase (MTHFR) is known to be irre- versible in vivo. Once 5 methyl THF has been formed in a cell, the only way that it can partici- pate in future purine or pyrimidine biosynthesis is by being used by methionine synthase, whose activity is absent or severely compromised if its essential cofactor, vitamin B12, is deficient.

This resultant trapping of folate in a cell as 5 methyl THF eventually reduces the folate cofac- tors involved in purines and pyrimidine biosyn- thesis to where this reduction produces the exact same megaloblastic anemia as that seen in folate

deficiency (1). In other words, while vitamin B12

deficient cells have adequate folate, it is trapped in a particular metabolic form and results in a sort of pseudo folate deficiency. The cell has adequate 5 methyl THF and one might thus anticipate that it would have a normal methylation cycle (Figure

9.1). However, this cycle is compromised because

it also needs vitamin B12 dependent methionine

synthase. The latter causes the very dramatic neu- ropathy seen in B12deficiency. This is due to a

reduction in the activity of one of the many methyltransferase in the cell that must, in a way that is as yet unclear, be involved in the mainte- nance of the myelin sheath (4). This neuropathy initially affects the peripheral nerves, but will eventually result in degeneration of the spinal col- umn. The clinical manifestation of this is in an initial peripheral neuropathy progressing to ataxia, paralysis and if left untreated, ultimately death. The fully developed condition is called subacute combined degeneration (SCD). The change in the peripheral nerves and central nerv- ous system are seen as a progression to demyeli- nation, described in its latter stages in the spinal tracts as a “field of holes.” Such demylelination can only be demonstrated at post mortem. The signs and symptoms in early stages of SCD are somewhat nonspecific and overlap to a significant extent with similar problems seen with advancing years. The features common to both would be memory loss, impaired mobility and general cog- nitive decline. The neuropathy can be detected clinically by a careful medical examination of neurological responses. Mostly from earlier examples of descriptions of patients with PA, it is estimated that about one third present the neu- ropathy only, one third the anemia and one third both. The concern is thus: if the anemia is treated or masked by an inappropriate administration of folic acid, as discussed below, its diagnosis, based on the neuropathy, will be absent in some patients until it has progressed to where it may be irre- versible. In addition, it will be difficult to diagnose in many patients because its signs and symptoms will be confused with those of advancing years.

One would anticipate that folate deficiency would also compromise the methylation cycle and produce a similar neuropathy (Figure 9.1), but for reasons that are unclear the neuropathy is not a usual presenting feature of folate deficiency. This may be because nerve tissue concentrates folate over other cell types. Only one study found this neuropathy characteric of vitamin B12defi-

ciency in a group of patients that had severe and prolonged folate deficiency (5).

Appropriate treatment of folate deficiency, either with food folate but more usually with the synthetic form of the vitamin folic acid, produces a complete remission of the anemia. Likewise, treatment of vitamin B12deficiency with vitamin

B12produces a complete remission of the anemia.

The neuropathy will also respond, but if it is very advanced some of the neural damage to the spinal column may not completely redress, leaving some residual neurological damage. If the vita- min B12deficiency is nutritional, as in a vegan’s,

additional vitamin B12, either by way of fortifica-

tion or more usually by supplements, can be effective. If the malabsorption is due to absence of the intrinsic factor needed for absorption, then vitamin B12 treatment must be parenteral. A

potentially serious issue arises if folic acid is used inappropriately to treat what in fact is vitamin B12

deficiency. What is seen to happen clinically is that the continuous ingestion of folic acid pro- duces the folate cofactors needed for purine and pyrimidine biosynthesis. Thus, in such subjects DNA biosynthesis will be normalized and an ane- mia will appear to be successfully treated. How- ever, the methylation cycle will continue to be compromised with a continuation of the neuropa- thy, to where it will present later at a much more advanced stage and at a point where it may largely be irreversible. This so-called masking of the anemia of vitamin B12deficiency results in an

anemia where the most easily recognizable signs and symptoms of vitamin B12deficiency do not

emerge. The neuropathy is much more difficult to diagnose and its presence is frequently confused

with the advancement in years, where of course the problem of vitamin B12 deficiency is most

prevalent. Thus, such vitamin B12 deficient

patients inappropriately receiving folic acid treat- ments may go undiagnosed (1).

The interaction of folic acid on the diagnosis of vitamin B12deficiency as documented above is

universally accepted. What is more controversial is the suggestion that the administration of folic acid may exacerbate the neuropathy, accelerating its rate of progression. This contention comes from the clinical description of the progression of the neuropathy described in the earlier case reports, where folic acid had been administered inappropriately (3, 4). Phrases such as an “explo- sive” progression of the neuropathy are used. Since the clinicians involved were some of the leaders of the day in the study of PA, it is very credible that they would have been able to recog- nize such a phenomenon. However since they were not blinded to the presence or absence of the alternative treatment, it is really impossible to say.