Deoxyadenosyl cobalamin is required as a coenzyme in the isom-erization of methylmalonyl CoA to succinyl CoA. In patients with cobalamin deficiency sufficient to cause anaemia or neuropathy, the serum methylmalonate (MMA) level is raised. Sensitive methods for measuring MMA and homocysteine in serum have been introduced and recommended for the early diagnosis of cobalamin deficiency, even in the absence of haematological abnormalities or subnormal levels of serum cobalamin or folate. Serum MMA fluctuates, however, in patients with renal failure. Mildly elevated serum MMA and/or homocysteine levels occur in up to 30% of apparently healthy volunteers, with serum cobalamin levels up to 350 ng/L and normal serum folate levels; 15% of elderly subjects, even with cobalamin levels > 350 ng/L, have this pattern of raised metabolite levels. These findings bring into question the exact cut-off points for normal MMA and homocysteine levels. It is also unclear at present whether these mildly raised metabolite levels have clinical consequences and how many of the subjects will progress to clinically overt cobalamin deficiency. When cobalamin supplies to the cell are suboptimal, there may be preferential use as methylcobalamin for methionine synthesis compared with ado-cobalamin for MMA metabolism. Urine MMA excretion may also be used to screen for cobalamin deficiency but this also is increased in aminoaciduria (e.g. Fanconi's syndrome).
Homocysteine exists in plasma as single molecules, as two molecules linked together (homocystine) and as mixed homo-cysteine-cysteine disulphides. Serum homocysteine levels are raised in both early cobalamin and folate deficiency, but they may be raised in other conditions, e.g. chronic renal disease, alcoholism, smoking, pyridoxine deficiency, hypothyroidism therapy with steroids, cyclosporin and other drugs. Levels are also higher in serum than in plasma, in men than in premenopausal women, women taking hormone replacement therapy or oral contraceptive users and in elderly subjects and patients with several inborn errors of metabolism affecting enzymes in trans-sulphuration pathways of homocysteine metabolism. Thus, homocysteine levels are not widely used for diagnosis of cobalamin or folate deficiency. Homocysteine levels are useful, however, in thrombophilia screening and in assessing for cardiovascular risk factors (see Chapter 58).
The principal methods used in diagnosing the cause of cobal-amin deficiency are listed in Table 5.7. Many of these tests are mentioned elsewhere in this chapter, and others are described in texts of gastroenterology. Studies of cobalamin absorption are, however, of particular importance.
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