Page 632 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 39 Megaloblastic Anemias 541

cobalamin malabsorption. 15,22 The physician must ensure that the
Practicing Classic Medicine Without the (Classic) Schilling Test
patient is compliant and demonstrates adequate cobalamin levels as
The Schilling test was used to identify the locus of cobalamin malab- well as resolution of hematologic and neurologic abnormalities on
sorption and, in some instances, such as pernicious anemia or bacte- follow-up. For nutritional cobalamin deficiency (e.g., vegetarians)
rial overgrowth, the cause of cobalamin deficiency. However, this test when the entire circuitry in cobalamin absorption is intact, daily oral
has been unavailable since 2003 in the United States. Although use cobalamin of 5 to 10 µg (found in conventional multivitamin tablets
of combined anti-IF antibodies and newer antiparietal cell antibodies in the United States) taken for a lifetime of vegetarianism will suffice.
yields an overall 73% sensitivity while maintaining 100% specificity for However, if malabsorption of food-bound cobalamin is suspected
pernicious anemia, 169 there remain difficulties in differentiating patients (especially in the elderly with achlorhydria), higher doses of daily oral
with all other causes of cobalamin malabsorption. A minimalist approach cobalamin (equal to or greater than 1000 µg/day) is required. 263
is to work around the nonavailability of the Schilling test and use a The bioavailability of oral cobalamin can be reduced by about
classic clinical approach to rule out potential differential diagnoses of
cobalamin deficiency (see box on Etiopathophysiologic Classification of 40% when it is taken with a meal; taking cobalamin on an empty
Cobalamin Deficiency). For example, most conditions predisposing to stomach will lower losses in the stool. More than 98% of all the
cobalamin deficiency should be clinically manifest by the time cobala- cobalamin in feces is in the form of cobalamin analogues, and about
min deficiency is evident. It should therefore be possible to identify 80% of the ingested cobalamin is converted to analogues by micro-
several conditions through a detailed dietary history or past medical organisms in the gut. 264
history, travel history, and drug history to suggest a dietary cause, Oral folate (folic acid) at doses of 1 to 5 mg/day results in adequate
esophagogastroduodenal disease, pancreatic insufficiency, impaired absorption (even where intestinal malabsorption of physiologic food
bowel motility, or other autoimmune diseases. The history and physical folate is present). Therapy should be continued until complete
examination could provide further leads and suggest additional focused hematologic recovery is documented. If the underlying cause leading
laboratory testing for rare conditions (stool for ova, anti–tissue transglu-
taminase antibodies, lipase, gastrin, intestinal biopsy, or radiographic to folate deficiency is not corrected, folate may be continued. Folinic
contrast studies for stasis, strictures, fistulas). With no further leads, acid (i.e., 5-formyl-THF [leucovorin]) should be reserved only for
and therefore by default, one can assume that the diagnosis is either rescue protocols involving antifolates (methotrexate or trimethoprim-
pernicious anemia or food-cobalamin malabsorption, which are both sulfamethoxazole), for 5-fluorouracil modulation protocols, after
treated with similar replacement doses of cobalamin. For the younger nitrous oxide toxicity, or in pediatric cases involving cerebral folate
patient with megaloblastic anemia, differentiating juvenile pernicious deficiency or inborn errors of folate metabolism. It is too expensive
anemia and congenital IF deficiency would warrant measurement of for conventional repletion in folate-deficient states in adults.
gastric juice for IF and achlorhydria, deoxyribonucleic acid (DNA) for
gastric IF can identify hereditary megaloblastic anemia, and DNA for
mutations in cubam receptor (amnionless/cubulin genes) could identify Response to Replenishment
Imerslund-Gräsbeck syndrome.
Thus the history, physical findings, and focused laboratory tests
with careful clinical follow-up can potentially identify the cause of the The response of the patient to appropriate replacement is reversion
majority of cases of cobalamin deficiency and bypass the need for a of megaloblastic hematopoiesis to normal hematopoiesis within the
Schilling test. first 12 hours; by 48 hours, normal hematopoiesis is reestablished,
and the only evidence for a prior megaloblastic state may be the
persistence of a few giant metamyelocytes. Because megaloblastosis
has been prolonged, expect associated cobalamin deficiency to ensue caused by cobalamin or folate deficiency can be reversed in 24 hours
(special emphasis should be given to identifying subtle manifestations by administration of folate (i.e., a nutritious hospital meal), delay of
of neurologic disease). If cobalamin deficiency is suspected, test for a diagnostic bone marrow aspirate should be avoided. Clinically the
both serum anti-IF antibodies and the newer more sensitive antipa- first 36 to 48 hours are often highlighted by the awakening of an
rietal cell antibodies (see section on Pernicious Anemia.) Also see box occasional semistuporous individual whose “chief complaint” is
on Practicing Classic Medicine Without the (Classic) Schilling Test. amazement at the remarkably improved sense of well-being experi-
enced, with increased alertness and appetite and reduced soreness of
the tongue. The elevated serum MMA and homocysteine levels will
THERAPY return to normal by the end of the first week.
Accelerated turnover of normal DNA in erythroid precursors is
Routinely, treatment with full doses of parenteral cobalamin (1 mg/ associated with an increase in serum urate level, which usually peaks
day) and oral folate (folic acid) (1 to 5 mg) before knowledge of the by the fourth day, and with increased cellular phosphate uptake for
type of vitamin deficiency is established should be reserved for the nucleotide synthesis. This may precipitate an attack of gout if the
severely ill patient. An appropriate regimen for conditions in which patient has a “gouty predisposition.” The reticulocyte count increases
cobalamin replenishment can correct cellular cobalamin deficiency by the second to third days and peaks by the fifth to eighth days (the
(but not correct the underlying problem that led to the deficiency, peak reticulocyte count is directly proportional to the degree of
such as pernicious anemia) is 1 mg of intramuscular or subcutaneous preexisting anemia). This is followed by a rise in RBC count, hemo-
cyanocobalamin per day (week 1), 1 mg twice weekly (week 2), 1 mg/ globin, and hematocrit by the end of the first week, which normalizes
week for 4 weeks, and then 1 mg per month for life (about 15%, or in approximately 2 months, regardless of the initial degree of anemia.
150 µg, is retained 48 hours after each 1-mg cobalamin injection). By the end of the third week, the RBC count should be above 3 ×
6
3
Ideally, this protocol for rapid correction of cobalamin deficiency and 10 /mm ; if it is not, additional causes of underlying iron deficiency,
complete replenishment of cobalamin stores should be used in the begin- hemoglobinopathy, chronic disease, or hypothyroidism should be
ning for all patients with cobalamin deficiency, regardless of the etiology considered (Table 39.7).
(see box on Modified Therapeutic Trials). Hypersegmented PMNs continue to remain in the blood for 10
Parenteral hydroxocobalamin should be reserved for all inborn to 14 days; however, the number of normal PMNs and platelets rises
errors of cobalamin metabolism. There is no major advantage of other and normalizes within the first week. During this process, there may
preparations over generic cyanocobalamin. There is equivalence be a transient left shift to include myeloid precursors. The reduced
between oral 2-mg cobalamin tablets consumed daily (where cobala- intramedullary hemolysis (as a result of normalized hematopoiesis)
min is passively absorbed at high doses) and traditional monthly leads to a gradual reduction in the serum bilirubin level by the end
parenteral treatment with 1 mg of intramuscular/subcutaneous of the first week, and LDH levels will drop concomitantly.
cobalamin among those requiring long-term cobalamin. So for In response to cobalamin, progression of neurologic damage and
patients who refuse monthly parenteral therapy, or prefer daily oral dysfunction is inhibited. In general, the degree of functional recovery
therapy, or in those with disorders of hemostasis, cobalamin (1 to is inversely related to the extent of disease and duration of signs and
2 mg/day as tablets) can be recommended for all those patients with symptoms. As a rough estimate, signs and symptoms that have been