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Megaloblastic Anemias (CAUSES OF COBALAMIN DEFICIENCY: u malabsorption;…

- - - - Folic acid supplements at time of conception & in first 12 w reduce by ~70% incidence of NTDs (anencephaly, meningomyelocele, encephalocele, and spina bifida)
        Most of this achieved by taking folic acid, 0.4 mg daily, at time of conception
      - incidence of cleft palate & harelip also reduced by prophylactic folic acid
        NTDs also caused by antifolate & antiepileptic drugs
      - underlying maternal folate metabolic abnormality:
        reduced activity of 5,10-methylene-THF reductase caused by a common C677T polymorphism in MTHFR gene; polymorphism codes for a thermolabile form of MTHFR; homozygous state--> lower mean serum and RBC folate level, also significantly higher serum homocysteine
        Serum vit B12 also lower in sera of mothers of NTD infants
        maternal TC II R polymorphisms a. w/ incr risk of NTD births
        no studies however, showing dietary fortification w/ vit B12
        reduces incidence of NTDs
    - - Cobalamin deficiency--> bilateral peripheral neuropathy or degeneration (demyelination) of post & pyramidal tracts of spinal cord and, less frequently, optic atrophy or cerebral symptoms
      - px, more freq male, presents w/ paresthesias, muscle weakness, or difficulty in walking and sometimes dementia, psychotic disturbances, or visual impairment
        Long-term nutritional cobalamin deficiency in infancy--> poor brain development & impaired intellectual development
        Folate deficiency suggested--> organic nervous disease, but uncertain
      - important clinical problem: nonanemic px w/ neurologic or psychiatric abnorms & a low or borderline serum cobalamin: necessary to establish whether significant cobalamin deficiency, e.g., by careful examination of blood film, tests for serum gastrin level and for Abs to IF or parietal cells, along w/ serum methylmalonic acid (MMA) measurement if available
        A trial of cobalamin therapy for min 3 m u also needed to determine whether symptoms improve
      - cobalamin neuropathy occurrence in absence of methylmalonic aciduria in TC II deficiency--> neuropathy related to defect in homocysteine-methionine conversion
        Accumulation of S-adenosylhomocysteine in brain--> inhibition of transmethylation reactions
      - Psychiatric disturbance common in both folate & cobalamin deficiencies
        like neuropathy, attributed to a failure of synth of SAM (needed in methylation of biogenic amines (e.g., dopamine) and of prs, PLs, and NTs in brain)
        A. betw lower serum folate or cobalamin & higher homocysteine & development of decr cognitive function and dementia in Alzheimer’s reported
        but supplementation w/ vit B12, vit B6, and folic acid did not improve cognitive function
- - - - In Cbl deficiency sufficient to cause anemia or neuropathy: serum MMA raised
        MMA and homocysteine recommended for early dx, even in absence of hematologic abnorms or subnormal Cbl
        Serum MMA fluctuate, however, in pxs w/ renal failure
        findings bring into question exact cutoff points for normal MMA and homocysteine levels
        also unclear whether these mildly raised metabolite levels have clinical consequences.
      - Serum homocysteine raised in both early cobalamin and folate deficiency but may be raised in other conditions, e.g., chronic renal disease, alcoholism, smoking, pyridoxine deficiency, hypothyroidism, and therapy with steroids, cyclosporine, and other drugs
        also higher in serum than in plasma, in men than in premenopausal women, in women taking hormone replacement therapy or in OCP users, and in elderly persons and patients w/ several inborn errors of metabolism affecting Es in trans-sulfuration pathways of homocysteine metabolism