Megaloblastic Anemias

Chapter 448 Megaloblastic Anemias



Norma B. Lerner



Megaloblastic anemia is a macrocytic anemia characterized by ineffective erythropoiesis, a kinetic term that describes active erythropoiesis associated with premature cell death and decreased red blood cell (RBC) output from the bone marrow. The RBCs are larger than normal at every developmental stage, and maturational asynchrony between the nucleus and cytoplasm of erythrocytes is present. The delayed nuclear development becomes increasingly evident as cell divisions proceed. Myeloid and platelet precursors are also affected, and giant metamyelocytes and neutrophil bands are often present in the bone marrow. There is usually an associated thrombocytopenia and leukopenia. The peripheral blood smear is notable for large, often oval, RBCs, with increased mean corpuscular volume (MCV). Neutrophils are characteristically hypersegmented, with many having >5 lobes. Almost all cases of childhood megaloblastic anemia result from folic acid or vitamin B12 deficiency; rarely, they may be caused by inborn errors of metabolism. Because folate and vitamin B12 are both required for the manufacture of nucleoproteins, deficiencies result in defective DNA and, to a lesser extent, RNA and protein synthesis. Megaloblastic anemias resulting from malnutrition are relatively uncommon in the USA but are important worldwide (Chapters 1 and 43).



448.1 Folic Acid Deficiency



Norma B. Lerner



Folic acid, or pteroylglutamic acid, consists of pteroic acid conjugated to glutamic acid. Biologically active folates are derived from folic acid and serve as one-carbon donors and acceptors in many biosynthetic pathways. As such, they are essential for DNA replication and cellular proliferation. Like other mammals, humans cannot synthesize folate and depend on dietary sources, including green vegetables, fruits, and animal organs (e.g., liver, kidney). Folates are heat labile and water soluble, and consequently boiling or heating folate sources leads to decreased amounts of vitamin. Naturally occurring folates are in a polyglutamated form that is less-efficiently absorbed than the monoglutamate species (i.e., folic acid). Dietary folate polyglutamates are hydrolyzed to simple folates that are absorbed primarily in the proximal small intestine by a specific carrier-mediated system. There is an active enterohepatic circulation. Folic acid is not biologically active and is reduced by dihydrofolate reductase to tetrahydrofolate, which is transported into tissue cells and polyglutamated. Because body stores of folate are limited, megaloblastic anemia will occur after 2-3 mo on a folate-free diet.



Etiology


Folic acid deficiency can occur as a consequence of inadequate folate intake, decreased folate absorption, or acquired and congenital disorders of folate metabolism.



Inadequate Folate Intake


Anemia due to decreased folate intake usually becomes manifest in the context of clinical conditions that are associated with increased vitamin requirements (e.g., pregnancy, growth in infancy and childhood, chronic hemolysis). Folate requirements increase markedly during pregnancy, in part to meet fetal needs, and deficiencies are common in mothers, particularly those who are poor or malnourished. Folate supplementation is recommended from the start of pregnancy to prevent neural tube defects and to meet the needs of the developing fetus. Fortunately, folate-deficient mothers generally do not give birth to infants with clinical folate deficiency because there is selective transfer of folate to the fetus via placental folate receptors.


Rapid growth after birth increases demands for folic acid. Human breast milk, infant formulas, and pasteurized cow’s milk provide adequate amounts of folic acid. Goat’s milk is deficient, and supplementation must be given when it is the child’s main food. Unless supplemented, powdered milk may also be a poor source of folic acid. Infants who are premature or ill and those with certain hemolytic disorders will have higher folate requirements.


Malnutrition is the most common cause of folate deficiency in older children. Those with hemoglobinopathies, infections, and/or malabsorption are at increased risk.



Decreased Folate Absorption


Malabsorption due to chronic diarrheal states or diffuse inflammatory disease can lead to folate deficiency. In both situations, some of the decreased folate absorption may be caused by impaired folate conjugase activity. Chronic diarrhea also interferes with the enterohepatic circulation of folate, thereby enhancing folate losses because of rapid intestinal passage. Megaloblastic anemia due to folic acid deficiency can occur in celiac disease or chronic infectious enteritis and in association with enteroenteric fistulas. Previous intestinal surgery is another potential cause of decreased folate absorption.


Certain anticonvulsant drugs (e.g., phenytoin, primidone, phenobarbital) can impair folic acid absorption, and many patients treated with these drugs have low serum levels of folic acid. Frank megaloblastic anemia is rare and readily responds to folic acid therapy, even when administration of the offending drug is continued. Alcohol overuse has also been associated with folate malabsorption.



Congenital Abnormalities in Folate Transport and Metabolism


Inborn errors of folate transport or metabolism are rare but can be life threatening. Those associated with megaloblastic anemia include hereditary folate malabsorption and certain extremely uncommon enzyme deficiencies. Hereditary folate malabsorption (HFM) has been associated with an inability to absorb folic acid, 5-tetrahydrofolate, 5-methyltetrahydrofolate, or 5-formyltetrahydrofolate (folinic acid). It can become apparent at 2-6 mo of age with megaloblastic anemia and other deficits resulting from folate deficiency. Serum and cerebrospinal fluid (CSF) folate levels are very low, with a loss of the normal 3 : 1 ratio of CSF to serum folate. Several loss-of-function mutations have been identified in the protein-coupled folate transporter (PCFT/SLC46A1) gene in patients with HFM. The megaloblastic anemia in HFM can be reversed with relatively low levels of serum folate, but folate sufficiency should be maintained in both the blood and the CSF to avoid other important complications. Adequate CSF levels may be particularly difficult to achieve, and very large oral doses, parenteral folate, or intrathecal folate may be needed. Though methylenetetrahydrofolate (MTHFR) deficiency is the most common inborn error of folate metabolism, severe cases produce a number of neurologic and vascular complications, but these are not associated with megaloblastic anemia.



Drug-Induced Abnormalities in Folate Metabolism


A number of drugs have anti–folic acid activity as their primary pharmacologic effect and regularly produce megaloblastic anemia. Methotrexate binds to dihydrofolate reductase and prevents formation of tetrahydrofolate, the active form of folate. Pyrimethamine, used in the therapy of toxoplasmosis, and trimethoprim, used for treatment of various infections, can induce folic acid deficiency and, occasionally, megaloblastic anemia. Therapy with folinic acid (5-formyltetrahydrofolate) usually is beneficial.



Clinical Manifestations


Mild megaloblastic anemia has been reported in very-low-birthweight infants, and folic acid supplementation is advised. Although rare nowadays, megaloblastic anemia due to folate deficiency has its peak incidence at 4-7 mo of age, somewhat earlier than iron-deficiency anemia, although both conditions may be present concomitantly in infants with poor nutrition. Besides the usual clinical features of anemia, folate-deficient infants can have irritability, chronic diarrhea, and poor weight gain. Hemorrhages from thrombocytopenia can occur in advanced cases. Congenital folate malabsorption and other rare etiologies of folate deficiency may be further associated with hypogammaglobulinemia, severe infections, failure to thrive, neurologic abnormalities, and cognitive delays.



Laboratory Findings


The anemia is macrocytic (mean corpuscular volume >100 fL). Variations in RBC shape and size are common (see Fig. 441-2). The reticulocyte count is low, and nucleated RBCs demonstrating megaloblastic morphology often are seen in the blood. Neutropenia and thrombocytopenia may rarely be present, particularly in patients with long-standing and severe deficiencies. The neutrophils are large, some with hypersegmented nuclei. Normal serum folic acid levels are 5-20 ng/mL; with deficiency, levels are <3 ng/mL. Levels of RBC folate are a better indicator of chronic deficiency. The normal RBC folate level is 150-600 ng/mL of packed cells. Levels of iron and vitamin B12

Only gold members can continue reading. Log In or Register to continue

Related posts:

  1. Embryology, Anatomy, and Function of the Esophagus
  2. Hereditary Predisposition to Thrombosis
  3. Bleeding
  4. Cystic Diseases of the Biliary Tract and Liver

Stay updated, free articles. Join our Telegram channel
Tags:
Jun 18, 2016 | Posted by in PEDIATRICS | Comments Off on Megaloblastic Anemias

Full access? Get Clinical Tree
Get Clinical Tree app for offline access