Page 631 - Hematology_ Basic Principles and Practice ( PDFDrive )

540 Part V Red Blood Cells

for presumed cobalamin or folate deficiency. The immediate question
Diagnostic Bone Marrow Aspiration
therefore pertains to the overall status of the patient.
Is bone marrow aspiration always necessary to diagnose cobalamin- or If the patient is decompensated or decompensation is imminent,
folate-deficient megaloblastosis? With the addition of highly sensitive obtain serum folate and cobalamin levels and bone marrow aspiration
serum tests for the specific diagnosis of cobalamin and folate defi- to confirm megaloblastosis and proceed with transfusion of 1 unit of
ciency, the need for a bone marrow test is often dictated by the packed RBCs slowly, with vigorous diuretic therapy to obviate further
urgency to diagnose megaloblastosis (with results available in an congestive heart failure from fluid overload; this mandates close
hour). For example, in the case of florid hematologic disease with or monitoring and correction of fluid and electrolyte imbalance.
without neurologic disease suggestive of cobalamin or folate deficiency, Cobalamin and folate should be administered simultaneously in full
bone marrow aspiration carried out as soon as possible is invaluable doses. Transfusion does not alter serum folate or cobalamin levels.
in assisting the rapid diagnosis of megaloblastosis. However, in the If the patient is moderately symptomatic (but not in heart failure),
outpatient setting, when the patient has a characteristic peripheral
smear, or for a patient with a primary neuropsychiatric presentation, a the strong likelihood of a dramatic response (in the sense of well-
case can be made to initiate the sequence of diagnostic tests without being and relief of sore tongue) within 2 to 3 days even before
bone marrow aspiration by proceeding with measurement of serum hematologic improvement argues against immediate blood transfu-
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levels of vitamins or metabolites (see Table 39.2). In a pregnant sion. Therefore (and provided the patient is unlikely to decompen-
patient with pancytopenia with macro-ovalocytes, hypersegmented sate in the short-term) proceed with appropriate diagnostic workup
polymorphonuclear neutrophils, and reticulocytopenia with a history of as for the well-compensated patient.
noncompliance with prenatal supplements (and no neurologic findings If the patient is well compensated and in the outpatient setting, the
suggestive of cobalamin deficiency), bone marrow aspiration may not physician has time to develop an orderly sequence of diagnostic tests.
be necessary to initiate therapy for a strong presumptive diagnosis of First, check the peripheral smear and rule out other macrocytic
folate deficiency. If there is no evidence of response within 10 days,
bone marrow aspiration is indicated. anemias (thin macrocytes with a normoblastic marrow in contrast to
macro-ovalocytes) (see Fig. 39.7). Draw blood for cobalamin and
folate levels (before the patient’s first hospital meal) to sort out whether
the problem is caused by a deficiency of folate or cobalamin, or both,
bone marrow. This occurs when there is a coexisting condition that or some other deficiency (see Table 39.2). Assuming that there is no
neutralizes the tendency to generate megaloblastic cells (usually urgency to make the diagnosis, the physician can elect to wait for the
involving reduction in RBC hemoglobinization, as in iron deficiency results of these tests before proceeding with the next test in the
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or thalassemia). A wide RBC distribution width (RDW) on the diagnostic workup. If making the diagnosis is urgent, a cost-effective
Coulter counter readout in the presence of a “normal” mean corpus- test is the bone marrow aspirate; results indicating megaloblastosis
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cular hemoglobin or MCV may reflect megaloblastic anemia or (or not) can be available within an hour. If bone marrow aspiration
dimorphic anemia (macro-ovalocytes plus microcytic hypochromic is performed, samples are sent for special stains and flow cytometry
RBCs). Because megaloblastic white blood cells and precursors are (megaloblastic erythropoiesis can resemble erythroleukemia) and
unaffected by deficient hemoglobinization, these pathognomonic cytogenetic analysis (myelodysplastic syndromes can exhibit some
findings (giant myelocytes and metamyelocytes, and hypersegmented megaloblastic changes in the erythroid series, but megaloblastic
PMNs) remain; the latter may persist for up to 2 weeks after replace- granulopoiesis is not seen). If the marrow is not obviously megalo-
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ment with cobalamin or folate. The recognition of masked mega- blastic but the iron stain reveals absent stores, review the morphologic
loblastosis should initiate investigations to rule out iron deficiency, evaluation again with special emphasis on granulocytic precursors and
anemia of chronic disease, or hemoglobinopathies. Appropriate promegaloblasts, and look for more subtle megaloblastic changes.
replacement with cobalamin or folate elicits a maximal therapeutic If the serum cobalamin and folate levels are equivocal (i.e., in the
benefit only when iron deficiency is corrected. Conversely, if com- low-normal range), and the patient elects to delay or refuses a bone
bined iron and cobalamin deficiency (total gastrectomy or pernicious marrow aspiration, a strong case can be made to test for serum
anemia) or iron and folate deficiency (pregnancy) is treated with iron homocysteine and MMA. Serum MMA and homocysteine levels are
alone, megaloblastosis will be unmasked. ordered together (the same sample remaining from the serum sent
for cobalamin and folate levels may be used if it was frozen). Integrat-
APPROACH TO DIAGNOSIS AND THERAPY OF ing the results for serum MMA and homocysteine levels (which will
be available after a week or more) with those for serum cobalamin
MEGALOBLASTOSIS and folate levels can help distinguish cobalamin and folate deficien-
cies (see Table 39.2). A normal MMA and homocysteine level elimi-
In general, there are three stages in approaching a patient: recognizing nates cobalamin deficiency with 100% confidence, and normal
that megaloblastic anemia is present; distinguishing whether folate, homocysteine levels suggest that megaloblastic anemia is not caused
cobalamin, or combined folate and cobalamin deficiencies have led by folate deficiency. These tests are particularly useful if the patient
to the anemia; and diagnosing the underlying disease and mechanism has pure neurologic disease or if there are associated conditions such
causing the deficiency. Establishing that the patient does have mega- as iron deficiency or thalassemia that can mask megaloblastosis.
loblastosis is, in theory, straightforward. This is easily done by first Administration of folate or cobalamin will reduce elevated serum
evaluating the complete blood count, the MCV, and the peripheral homocysteine and MMA levels to basal values by 1 week, so there is
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smear, followed by a bone marrow aspiration. Clues to whether only a narrow window to clinch the diagnosis using metabolite tests.
cobalamin or folate deficiency is responsible for megaloblastosis can In the rare situation when a defect in cobalamin or folate metabolism
be obtained by serum cobalamin and serum folate levels; if these levels is suspected, early consultation with experts who have published in
are borderline, additional testing of serum MMA and serum homo- this area is advised.*
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cysteine can define the true nature of the deficiency. However, this A reticulocyte count is useful to follow the patient’s response to
ideal and orderly workup is not always feasible in clinical practice, appropriate replacement therapy. Additional supporting studies to
because the patient may present for the first time with megaloblastosis document increased serum LDH, haptoglobin, and bilirubin (evi-
with or without associated neurologic disease; may be referred after dence for intramedullary hemolysis) may be performed.
a variable workup has already been initiated for possible megaloblas- When the megaloblastic state is established, try to determine the
tosis; may present with symptoms primarily attributed to a disease underlying mechanism of cobalamin or folate deficiency. The cause of
predisposing to cobalamin or folate deficiency; may present with a folate deficiency is usually sorted out by this time from the history,
disease associated with hyperhomocysteinemia (discussed later), in physical examination, and the clinical setting. If pure folate deficiency
which case anemia or neurologic dysfunction may only be a minor
symptom; may present with isolated neurologic disease in the absence
of anemia; or may be referred after empirical therapy has been given *References 18,19,46,164,165,175,176,234,261,262.