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604 Part VI: The Erythrocyte Chapter 41: Folate, Cobalamin, and Megaloblastic Anemias 605

intramuscular (IM) daily for 2 weeks, then weekly until the hematoc- persist for 10 to 14 days; (3) rise in serum cobalamin and folate. Cobal-
rit is normal, and then monthly for life. For neurologic manifestations, amin deficiency does not respond to a physiologic dose of folate (100 to
1000 mcg every 2 weeks for 6 months is recommended. Higher doses 400 mcg/day), although this dose produces a maximal response in folate
are given for certain inherited disorders (e.g., TC deficiency). Transfu- deficiency. Larger doses of folate (5 to 15 mg/day) can produce a reticu-
sion occasionally is required when the hematocrit is less than 15 per- locytosis and partially or temporarily correct the anemia in cobalamin
cent or the patient is debilitated, infected, or in heart failure. In such deficiency. To avoid the risk of masking an underlying cobalamin defi-
instances, packed cells should be given slowly to avoid pulmonary ciency by inducing a hematologic remission in response to folate, doses
edema. Infections can impair the response to cobalamin and must be in excess of 1 mg folic acid daily should be shunned until an underlying
treated vigorously. cobalamin deficiency has been ruled out. 3
Response to Treatment and Therapeutic Trial Special Circumstances
Following parenteral administration of cobalamin to deficient patients, After Gastrectomy Cobalamin should always be given after total gas-
elevated plasma bilirubin, iron, and LDH levels fall rapidly (Fig. trectomy. Cobalamin administration is not necessary after partial gas-
41–16). Decreasing plasma iron turnover and fecal urobilinogen trectomy, but patients need to be watched for megaloblastic anemia,
360
reflect cessation of ineffective erythropoiesis. Within 12 hours, the mar- bearing in mind that this anemia can be masked by postgastrectomy
row begins to change from megaloblastic to normoblastic, a process that iron deficiency. 352,362
is complete in 2 to 3 days. Consequently, morphologic diagnosis may be Blind Loop Syndrome The anemia of the blind loop syndrome
difficult after treatment is initiated. Reticulocytosis begins on days 3 to can be treated by parenteral cobalamin therapy. It also responds after
361
5 and peaks on days 4 to 10. The new red cells come from new nor- approximately 1 week to oral broad-spectrum antibiotics (cephalexin
moblasts, not from the old megaloblasts, most of which die before leav- monohydrate [Keflex] 250 mg QID plus metronidazole 250 mg TID for
363
ing the marrow. Blood hemoglobin concentration becomes normal 10 days), and cobalamin absorption is restored. Successful surgical
149
within 1 to 2 months. If normal values are not achieved by 2 months, correction of an anatomic lesion also cures the syndrome.
another cause of anemia should be sought. Fish Tapeworm Treatment consists of a single oral dose of a
Other changes include the following: (1) prompt and dramatic 50 mg/kg of niclosamide or a dose of 5 to 10 mg/kg of praziquantel.
improvement in the sense of well-being; (2) normalization of leuko-
cyte and platelet counts, although neutrophil hypersegmentation may Rekindled Use of Oral Cobalamin
364
Much interest has been kindled regarding the possibility of treating
cobalamin deficiency with oral cobalamin as had been proposed previ-
20 Vitamin B 12 ously. Oral cobalamin can be used not only for treatment of dietary
365
15 cobalamin deficiency that occurs in vegans and in patients with very
% 10 severe general malnutrition, but also for patients with food cobalamin
5 malabsorption and for patients with PA, provided the patients are fol-
366
0 100 Reticulocyte count lowed carefully. In patients lacking intrinsic factor, approximately 1
367
percent of an oral dose of the vitamin crosses the intestinal epithelium
mcg/100 mL 50 Serum iron by mass action. Therefore, 1000 to 2000 mcg/day of oral cobalamin sup-
plies most PA patients with their daily cobalamin requirement with-
out the need for injections and their accompanying pain and expense.
min deficiency and patients (e.g., hemophiliacs, the frail elderly) who
0.7 0 Cobalamin should be given by mouth to patients with dietary cobala-
0.6 cannot take IM injections.
mg/day 0.5 Bilirubin ACUTE MEGALOBLASTIC ANEMIA
0.4
0.3
0.2 Megaloblastic anemia usually is a chronic condition that requires weeks
0.1 or months to develop, but a potentially fatal megaloblastic state result-
0 ing from acute tissue folate or cobalamin deficiency can arise over the
course of only a few days. Patients with acute megaloblastic anemia
mg/day 600 Stool urobilinogen present with rapidly developing thrombocytopenia and/or leukopenia
400
and counts that sometimes fall to very low levels, but little change in red
200
0 cell levels unless another cause of anemia is present. The discrepancy
–6 –5 –4 –3 –2 –1 0123456789 between platelet and leukocyte counts on the one hand and red cells
50 Iron turnover on the other hand is a reflection of the much longer red cell life span.
The clinical picture can suggest an immune cytopenia. The diagnosis
mg/day 40 is made from the marrow aspirate, which is floridly megaloblastic, and
30
confirmed by the rapid response to appropriate replacement therapy.
20
10 The most common cause of acute megaloblastic anemia is nitrous
368
369
0 oxide (N O) anesthesia. N O rapidly destroys MeCbl, leading to a
2
2
–6 –5 –4 –3 –2 –1 012 3 456789 megaloblastic state. AdoCbl eventually is lost, SAMe and total folate
Day after therapy
levels decline, and the proportion of folate in the form of N -methyl-
5
tetrahydrofolate increases. Clinical findings develop quickly. Grossly
370
Figure 41–16. Effect of cyanocobalamin on reticulocyte count, 371
serum iron, serum bilirubin, stool urobilinogen, and plasma iron turn- megaloblastic changes are seen in the marrow after 12 to 24 hours.
over. (Adapted with permission from Coleman D, Donohue D, Finch C, Hypersegmented neutrophils do not appear until 5 days after expo-
372
et al: Erythrokinetics in pernicious anemia. Blood 11(9):807–820, 1956.) sure but then persist for several days. The effects of N O disappear
2
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