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602 Part VI: The Erythrocyte Chapter 41: Folate, Cobalamin, and Megaloblastic Anemias 603

Neuropsychiatric findings include peripheral neuropathy, gait distur- intestinal bacteria synthesize propionate, a precursor of methylmalo-
bance, memory loss, and psychiatric symptoms, often with abnormal nate, and in conditions of bacterial overgrowth, microbially derived
evoked potentials. Serum cobalamin may be normal, borderline, or low, methylmalonic acid may contribute to elevations in plasma methyl-
but tissue cobalamin deficiency is suggested by consistently high levels malonic acid. 351,352 Although measurement of these metabolites may be
of serum methylmalonic acid and/or homocysteine. Most of the neuro- used for population screening for evidence of cobalamin deficiency, the
psychiatric abnormalities appear to respond to cobalamin therapy. finding of an isolated elevation of plasma methylmalonate cannot be
taken as a priori evidence of clinically attributable cobalamin deficiency,
LABORATORY FEATURES absent any demonstration of a therapeutic response to the administra-
tion of cobalamin.
352, 353
Plasma or Serum Cobalamin Levels Spinal fluid methylmalonic acid levels are markedly elevated in
Plasma or serum cobalamin is low in most but not all patients with cobalamin deficiency. 354
cobalamin deficiency. Cobalamin levels are usually normal in cobala-
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min deficiency resulting from exposure to nitrous oxide, TC deficiency, Assays of Cobalamin Absorption and Intrinsic Factor
and inborn errors of cobalamin metabolism. Levels also may be normal Despite its numerous shortcomings the previous “gold standard” for
in cobalamin-deficient patients with high HC levels resulting from mye- assessment of cobalamin absorption was the Schilling test. The Schil-
loproliferative diseases. Conversely, plasma cobalamin levels may be low ling test assessed cobalamin absorption by measuring urinary radio-
in the presence of normal tissue cobalamins in vegetarians, in subjects activity after an oral dose of radioactive cobalamin. The test could be
taking megadoses of ascorbic acid, in pregnancy (25 percent), in the performed even after cobalamin deficiency had been corrected. The test
343
presence of HC deficiency, 344,345 and in megaloblastic anemia result- consisted of administering a physiologic dose of radiolabeled Co-CnCbl
ing from folate deficiency (30 percent). Plasma folate may be high by mouth followed 2 hours later by injection of a large “flushing” dose
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in cobalamin deficiency because of retardation in conversion of meth- of unlabeled CnCbl and determination and radioactivity in a 24-hour
yltetrahydrofolate, which is the predominant form in plasma. Patients collection of urine. Subjects with normal absorption excreted 7 per-
deficient in both cobalamin and folate may show normal serum folate cent or more of the radioactivity in the urine. Subjects with subnor-
levels. mal urinary excretion would have the test repeated with addition of an
animal-derived intrinsic factor to determine whether the malabsorp-
Plasma or Serum Holotranscobalamin tion could be corrected. The use of the Schilling test has dropped to
355
The fraction of the cobalamin in plasma that is bound to TC consti- a point of obsolescence as a consequence of reduced availability of the
tutes only 10 to 30 percent of the total plasma cobalamin. Even so, it is test components, cost, radioactive waste disposal, and concern about
this fraction that is functionally important and also better reflects the the use of animal-derived tissues for human use, which were required
64
integrity of the cobalamin absorptive status of an individual. 142,346,347 for the intrinsic factor administered in the second part of the test.
The major fraction of plasma cobalamin bound to HC is considered Replacements for the Schilling test are currently under development.
functionally inert and is therefore less relevant for the consideration of One approach uses measurement of the change in holoTC following
cobalamin status. Consequently, and with the development of assays to oral administration of non–radiolabeled cobalamin. 346,347,356 A different
measure the TC-bound fraction of the plasma cobalamin, an increasing approach involves the use of accelerator mass spectrometry and micro-
14
357
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body of evidence has accumulated to support the usefulness of TC-as- bially produced C at attomolar concentrations. In this approach, C
sociated cobalamin (holoTC). 64,137,140, 346 is measured in blood at the time of peak appearance 6 to 8 hours follow-
ing the dose. Both methods show promise but have not been approved
Methylmalonic Acid or validated for routine clinical use.
Except when caused by an inborn error, methylmalonic aciduria is a
reliable indicator of cobalamin deficiency. Normal subjects excrete Deoxyuridine Suppression Test
348
only traces of methylmalonate (0 to 3.4 mg/day). In cobalamin defi- The dU suppression test is based on the finding that unlabeled dU can
3
3
ciency, urine methylmalonate usually is elevated. Cobalamin therapy suppress the uptake of [ H]thymidine ([ H]Thd) into the DNA of cul-
349
restores excretion to normal in a few days. Another possible advantage tured lymphocytes or marrow cells through dilution of the label in the
358
of measurement of urine rather than plasma methylmalonic acid is that thymidine pool. This occurs when the thymidylate synthase reaction
in conditions of impaired renal function, when plasma methylmalonic is functionally intact, which requires adequate quantities of both folate
acid may give misleadingly elevated levels, measurement of the metab- and cobalamin.
olite in urine when correlated with creatinine obviates this problem. 350 The dU suppression test is chiefly a research tool. It can help diag-
nose certain special clinical problems, but these problems also can be
358
Serum or Plasma Methylmalonic Acid and Homocysteine diagnosed using other laboratory tests, therapeutic trials with vitamins
Elevated plasma or serum methylmalonic acid and homocysteine lev- or iron, or watchful waiting. Furthermore, in more than 40 years of use,
els are indicators of tissue cobalamin deficiency. Their levels are high in the test has not moved from the research laboratory into the clinic. The
more than 90 percent of cobalamin-deficient patients and rise before dU suppression test seems unlikely to enjoy more widespread clinical
plasma cobalamin falls to subnormal levels. 219,351 Elevated plasma meth- use in the future.
ylmalonic acid and/or elevated homocysteine are both indicators of
cobalamin deficiency in patients without a congenital disorder in their
metabolism. Of the two, methylmalonic acid measurement is both more THERAPY, COURSE, AND PROGNOSIS
sensitive and more specific, and elevated methylmalonic acid will per- Treatment of cobalamin deficiency consists of parenteral CnCbl (vita-
sist for several days, even after cobalamin treatment is instituted. Unlike min B ) or OHCbl to replace daily losses and refill storage pools, which
12
homocysteine levels that rise in folate and pyridoxine deficiencies, as normally contain 2 to 5 mg of cobalamin. Toxicity is highly unusual,
359
well as in hypothyroidism, methylmalonic acid elevation is seen only in and there is no defined upper limit. Doses exceeding 100 mcg saturate
2
cobalamin deficiency. In renal diseases however, both homocysteine the cobalamin-binding proteins (TC and HC), and the excess is lost in
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and methylmalonate, acid levels are frequently elevated. Additionally, the urine. A typical treatment schedule consists of 1000 mcg cobalamin

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