Page 617 - Hematology_ Basic Principles and Practice ( PDFDrive )

526 Part V Red Blood Cells

deep tendon reflexes with spasticity or muscle weakness, urinary or findings of combined immunodeficiency in hereditary folate
fecal incontinence, orthostatic hypotension, amaurosis, dementia, malabsorption. 112
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psychosis, or mood disturbances. Overall, although the neurologic
deficits were mild in most cases, the severity was judged related to
the duration of symptoms before diagnosis; not unexpectedly, those SPECTRUM OF CLINICAL PRESENTATIONS WITH
with the shorter duration of symptoms responded most to appropri- COBALAMIN DEFICIENCY
ate replacement.
The age-specific presentations with cobalamin deficiency are discussed
OTHER EFFECTS OF COBALAMIN AND in Nutritional Cobalamin Deficiency. Classic presentations of nutri-
tional cobalamin deficiency in developing countries are often
FOLATE DEFICIENCY accompanied by iron deficiency, and among malnourished popula-
tions, many will also have folate deficiency. Among vegetarians in
Cobalamin deficiency more often than folate deficiency can also developing countries, cases with nutritional cobalamin deficiency
result in sterility from the effects on the gonads. An unexplained may present in the second and third decades with pancytopenia, mild
finding is generalized melanin pigmentation that is reversible by hepatosplenomegaly, fever, and occasionally thrombocytopenic
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specific nutrient replenishment. Cobalamin deficiency negatively bleeding. Alternatively, a neurologic and psychiatric syndrome may
106
affects bone development and maintenance, which explains the develop with or independent of anemia. Because neuropsychiatric
reduced bone mineral density in those with cobalamin defi- presentations may dominate the clinical picture and the patient may
ciency 107,108 including pernicious anemia. 109,110 Folate is also impor- not have anemia, careful review of the peripheral smear may reveal
111
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tant for maintenance of regulatory T cells ; this may explain the macrocytosis. In over a quarter of patients with cobalamin neuropa-
thy in the United States, there was no reduction in the hematocrit
despite neurologic disease, and only a minority of patients had
combined hematologic and neurologic disease. Indeed, the higher the
hematocrit, the more severe the neurologic disorder! Conversely,
a anemic patients may have no neurologic deficits, and the level of
cobalamin may have no correlation with the existence or severity of
neurologic disease.
BIOCHEMICAL INDICATORS OF EVOLVING DEFICIENCY
b
b
Early manifestations of negative cobalamin balance are increased
serum methylmalonic acid (MMA) and total homocysteine levels
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(Table 39.2). This can occur when the total cobalamin in serum is
still in the low-normal range. Continued negative cobalamin balance
leads to an absolute decrease in serum cobalamin level. Normal levels
of MMA and homocysteine rule out clinically significant cobalamin
deficiency with virtually 100% certainty. 22
Fig. 39.8 SPINAL CORD IN COBALAMIN DEFICIENCY. The cross Likewise, metabolic evidence for folate deficiency (i.e., increased
section of the spinal cord stained with Luxol blue shows demyelination of serum total homocysteine level) can be found when serum folates are
the dorsal columns (a) and early demyelination of the lateral columns (b). still in the low-normal range.

TABLE Stepwise Approach to the Diagnosis of Cobalamin and Folate Deficiency
39.2
Megaloblastic Anemia or Neurologic-Psychiatric Manifestations Consistent with Cobalamin Deficiency Plus Test Results on Serum Cobalamin and Serum Folate
b
a
Cobalamin (pg/mL) Folate (ng/mL) Provisional Diagnosis Proceed with Metabolites? c
>300 >4 Cobalamin or folate deficiency is unlikely No
<200 >4 Consistent with cobalamin deficiency No
200–300 >4 Rule out cobalamin deficiency Yes
>300 <2 Consistent with folate deficiency No
<200 <2 Consistent with (1) combined cobalamin Yes
plus folate deficiency or (2) isolated
folate deficiency
>300 2–4 Consistent with (1) folate deficiency or Yes
(2) an anemia unrelated to vitamin
deficiency
Test Results on Metabolites: Serum Methylmalonic Acid and Total Homocysteine
Methylmalonic Acid Total Homocysteine Diagnosis
(Normal, 70–270 nM) (Normal, 5–14 µM)
Increased Increased Cobalamin deficiency confirmed; folate deficiency still possible (i.e., combined
cobalamin plus folate deficiency possible)
Normal Increased Folate deficiency is likely
Normal Normal Cobalamin and folate deficiency is excluded
a Serum cobalamin levels: abnormally low, less than 200 pg/mL; clinically relevant low-normal range, 200 to 300 pg/mL.
b Serum folate levels: abnormally low, less than 2 ng/mL; clinically relevant low-normal range, 2 to 4 ng/mL.
c Any frozen-over sample from serum folate/cobalamin determination can be subjected to metabolite tests.