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596 Part VI: The Erythrocyte Chapter 41: Folate, Cobalamin, and Megaloblastic Anemias 597

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Megaloblastic Anemia Misdiagnosed as Acute Leukemia milk, which is poor in available folate. Destruction of folate through
Occasionally, very severe megaloblastic anemia produces marrow mor- excessive cooking can aggravate folate deficiency.
phology so bizarre as to be mistaken for acute leukemia. In some cases, In alcoholic cirrhosis, megaloblastic anemia usually is caused by
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the erythroid series does not mature, and the megaloblastic pronor- folate deficiency. Alcohol may acutely depress serum folate, even if
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moblast dominates the marrow with prominent mitotic figures and dys- folate stores are replete, and accelerates the development of meg-
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morphic forms, raising the possibility of erythroid leukemia. aloblastic anemia in persons with early folate deficiency. Alcohol
causes acute marrow suppression, decreases in reticulocyte, platelet,
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Megaloblastic Changes in Other Cells and granulocyte levels ; reversible vacuolation of erythroid and mye-
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In most forms of megaloblastic anemia, cytologic abnormalities resem- loid precursors; and dysfunction of granulocytes. These changes
bling megaloblastosis may appear in other proliferating cells. Epithe- occur even if large doses of folate are given with the alcohol. 191
lial cells from the mouth, stomach, small intestine, and cervix uteri Decreased Intake Caused by Impaired Absorption Nontropi-
may look megaloblastic, appearing larger than their normal counter- cal Sprue Nontropical sprue (celiac disease in children) is related to
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parts and containing atypical immature-looking nuclei. Distinguishing ingestion of wheat gluten. Pathologically, nontropical sprue shows
these “megaloblastic” changes from the changes of malignancy may be atrophy and chronic inflammation of the small intestinal mucosa that
difficult. 168 is most severe proximally. Findings include weight loss; glossitis (typi-
cal of folate deficiency); other signs of a generalized vitamin deficiency;
Chemical Changes in Body Fluids diarrhea; and passage of light-colored, bulky stools with a particularly
Plasma bilirubin, iron, and ferritin levels are increased. Serum lac- foul odor caused by steatorrhea. Iron deficiency, hypocalcemia, osteo-
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tate dehydrogenase-1 (LDH-1) and LDH-2, both found in red cells, are porosis, and osteomalacia may occur.
markedly elevated as a result of rapid intramedullary erythroblast turn- Folate malabsorption occurs in most patients with this disor-
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over and increase with the severity of the anemia. In megaloblastic der. Serum folate levels are low, and megaloblastic anemia occurs
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anemia LDH-1 is greater than LDH-2, whereas in other anemias LDH-2 frequently.
is greater than LDH-1. Serum muramidase (lysozyme) levels are Tropical Sprue Tropical sprue is endemic in the West Indies,
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high, whereas serum glutamic oxaloacetic transaminase (aspartate southern India, parts of Southern Africa, and Southeast Asia. It can
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transaminase [AST]) is normal. Erythropoietin levels rise, but less be acquired by travelers to those regions and persists for many years
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than in other anemias of similar severity. Surprisingly, the elevated after the travelers return. Tropical sprue is rapidly corrected by folate
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erythropoietin levels fall sharply within 1 day of beginning treatment, therapy, even though folate deficiency does not cause the disease. The
an interval too short either to have been mediated by the hematocrit or precise etiology of tropical sprue is unknown, although the response of
to affect it. the disease to antibiotics suggests infection. 196
Clinically and pathologically, tropical sprue is like nontropi-
Cytokinetics cal sprue, except that tropical sprue is more severe in the distal small
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Megaloblastic anemia is associated with two pathophysiologic abnor- intestine. Therefore, tropical sprue eventually also leads to cobalamin
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malities: ineffective erythropoiesis and hemolysis. Ineffective erythro- deficiency and should be strongly considered as a cause of cobala-
poiesis increases the red cell precursor to reticulocyte ratio, plasma iron min deficiency in former residents of the tropics, even though they have
turnover, LDH-1 and LDH-2 levels, and “early labeled” bilirubin. been away from the tropics for 20 years or more. Folate malabsorption
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Both intramedullary and extramedullary hemolysis occurs in meg- may occur, possibly because the diseased intestine fails to deconjugate
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aloblastic anemia, with red cell life span decreased by 30 to 50 percent. 177 folate polyglutamates. Consequently, megaloblastic anemia is very
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Increased serum muramidase in megaloblastic anemia can be common in patients with this disease, and may result from both folate
caused by increased granulocyte turnover, possibly induced by disin- and cobalamin deficiency.
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tegration of granulocyte precursors in the marrow (ineffective granulo- Other Intestinal Disorders Malabsorption of folic acid com-
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poiesis). In cobalamin deficiency, platelet production is only 10 percent monly occurs in regional enteritis, after extensive resections of the
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of that expected from the megakaryocyte mass, perhaps reflecting small intestine, and in conditions such as lymphomatous or leukemic
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ineffective thrombopoiesis. Platelets in severe cobalamin deficiency are infiltration of the small intestine, Whipple disease, scleroderma and
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functionally abnormal. 179 amyloidosis, and diabetes mellitus. Systemic bacterial infections
impair folate absorption. 206
Increased Folate Requirements in Pregnancy During preg-
FOLIC ACID DEFICIENCY nancy (Chap. 8), folate requirements increase five- to 10-fold because
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Etiology and Pathogenesis of transfer of folate to the growing fetus, which draws down mater-
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Folate deficiency is caused by (1) dietary deficiency, (2) impaired nal folate stores even in the face of severe maternal folate deficiency.
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absorption, and (3) increased requirements or losses (see Table 41–4). Further increases in requirements may result from the presence of
Decreased Intake Caused by Poor Nutrition Prior to the mid- multiple fetuses, a poor diet, infection, coexisting hemolytic anemia,
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1990s, inadequate dietary intake was the major cause of folate defi- or anticonvulsant medication. Lactation aggravates folate deficiency.
ciency. However, in the era of folic acid fortification, the prevalence of Consequently, folate deficiency is very common in pregnancy and is the
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folate deficiency has fallen dramatically. In the United States, the prev- major cause of the megaloblastic anemia of pregnancy, particularly in
alence of low plasma folate has dropped from 22 to 1.7 percent of the developing countries. 212
population. Because folate reserves are limited, deficiency develops Folate deficiency is difficult to diagnose in pregnancy because the
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rapidly in malnourished persons, typically the old, the poor, and the signs of deficiency are obscured by the normal hematologic changes of
alcoholic. Folate deficiency can also occur during hyperalimentation pregnancy. During pregnancy, a physiologic “anemia” develops because
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and subclinical folate deficiency has been reported in subtotal gastrec- of increased plasma volume that is only partly offset by an accompa-
tomy. Folate deficiency can occur in premature infants, especially nying increase in red cell mass. Hemoglobin levels may fall to 10 g/dL.
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with infection, diarrhea, or hemolytic anemia ; in children on a syn- The anemia is associated with a physiologic macrocytosis; MCV may
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thetic diet because of inborn errors ; and in infants raised on goat’s increase to 120 fL, although the average at term is 104 fL. Serum
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