Pediatrics

B12 and folate deficiency anemias

OVERVIEW: What every practitioner needs to know

Are you sure your patient has B12 or Folate Deficiency Anemia? What are the typical findings for this disease?

Deficiencies of vitamin B12 and folate are causes of macrocytic anemia. However, most macrocytic anemias in children are not associated with either B12 or folate deficiency, but rather are associated with drug exposure.

B12 deficiency is very rare in the pediatric population of the United States. Practically speaking, it is seen only in several rare genetic disorders and in children who have had resection of their terminal ileum.

B12 deficiency can give rise to three clinical pictures in which either a megaloblastic anemia, GI symptoms, or neurologic degeneration predominate as described below.

Megaloblastic anemia due to B12 deficiency takes many months to develop because of the long half life and large hepatic stores of the vitamin. A severe macrocytic anemia (elevated MCV), accompanied by hypersegmented neutrophils, neutropenia, and thrombocytopenia eventually develops. Usually, patients will often have evidence of co-existing glossitis and GI symptoms.

In some patients with B12 deficiency, GI finds are most prominent. These may include glossitis, "canker" sores of the tongue, decreased appetite, and varying constipation and diarrhea.

Neurologic Disease due to B12 deficiency may present as "subacute combined degeneration of the spinal cord" (SCDSC). This is extremely rare in pediatric patients. It involves degeneration of the posterior and lateral columns of the cord, with the lower extremities more affected. Vibratory and position sense are affected first, with pyramidal tract signs developing later. Late manifestations can include optic atrophy, peripheral neuropathy, and dementia.

Folate deficiency in children is most commonly associated with a) significant malnutrition syndromes, b) conditions with increased folate demands such as occurs with chronic hemolytic anemias, or c) exposure to anti-folate drugs used for cancer chemotherapy, autoimmune, or rheumatologic diseases.

What other disease/condition shares some of these symptoms?

Patients with increased folate requirements associated with hemolytic anemia routinely receive folic acid 1mg daily. Although B12 and folate deficiency are usually considered with macrocytic anemias, B12 and folate deficiency in children in the developed world is rare. Most cases of macrycytic anemia are not caused by either B12 or folate deficiency.

Common causes of macrocytosis include: hypothryodism, exposure to anti-folate drugs, anti-seizure medications, and Down Syndrome. Hereditary orotic aciduria and thiamine-response anemia are very rare. Macrocytosis may also be noted along with aplastic anemia, Diamond-Blockfan anemia, obstructive liver disease, and myelodysplastic syndromes.

What caused this disease to develop at this time?

Vitamin B12 deficiency:

Inadequate gastric intrinsic factor

Disease of the small intestine

Inadequate nutrition

Transcobalomin II deficiency (rare)

Rare metabolic defects

Folate deficiency:

Defects in folate absorption

Inadequate nutrition

Increased requirements

Folate inhibitor drugs

Rare metabolic defects

Other causes of Megaloblastic Anemia:

Orotic acidura

Myelodysplasia, leukemia

Drug induced

Thiamine-responsive and pyridoxine-responsive anemias

B12 deficiency in pediatric patients is often due to abnormalities of the terminal ileum, which is where B12 is absorbed. This is most commonly due to surgical resection, Crohn's disease, or tropical and non-tropical sprue. B12 deficiency is rarely noted among strict vegetarians who fail to receive adequate supplementation.

Pernicious anemia is extremely rare in children and is caused by deficiency of gastric intrinsic factor which is needed for absorption of vitamin B12 from the gut. Pernicious anemia, with atrophy of the gastric mucosa, is probably an autoimmune disease, and is most common in the 5th through 7th decades of life. Pernicious anemia is also associated with achlorhydria, gastric resection surgery, and rare intrinsic factor mutations.

Folate deficiency is most commonly seen associated with defects in absorption, with rare inherited disorders, or infiltrative disease of the small bowel. Poor intake, such as with goat's milk diet, also may lead to folate deficiency. Increased metabolic requirements for folates may also lend to folate deficiency, but typically occurs only over an extended period. Hemolytic anemia (Hereditary Spherocytosis, sickle cell anemia) with marked reticulocytosis is a classic cause. Antifolates - methotrexate, trimethoprim, sulfones- may also lead to folate deficiency. Rare defects in purine and pyrimidine synthesis, such as orotic aciduria and methionine synthase deficiency, are rare causes.

Pathophysiology of B12 and folate deficiency

Pathophysiology:

Vitamin B12 most importantly functions as a coenzyme in two reactions:

1) the synthesis of methionine from homocystine, and

2) the conversion of methylmalonyl CoA to succinyl CoA.

Both of these reactions reduce the levels of two potentially toxic materials, homocystine and methylmalonate.

Folate is widespread in food, both in meats and in fruits and vegetables. Dietary folates are primarily absorbed in the small intestine. Folates bind to and act as coenzymes for enzymes which mediate single-carbon metabolism. In animals and humans, folates primarily exist as polyglutamates.

Folate deficiency is prevalent worldwide, coexisting with poverty, malnutrition, and parasitic diseases. Folate supplementation of food has become common in the developed world, particularly because of the association between folate deficiency and newborn neural tube defects.

What laboratory studies should you request to confirm the diagnosis? How should you interpret the results?

CBC:

Varying degrees of anemia will be seen. On peripheral smear the mature erythrocytes have abnormal shapes and are of various sizes, but the MCV is routinely increased.

Bone Marrow Aspiration/Biopsy:

Megaloblastic changes in bone marrow morphology can affect erythroid, myeloid and platelet precursors. Myeloid precursors are larger than normal, and increased lobulation of neutrophil nuclei (with six or more lobules) is also classically noted. Neutropenia and thrombocytopenia are more commonly noted in patients with severe B12 or folate deficiency anemia.

Vitamin B12 and Folate levels:

The most direct evidence of B12 deficiency is a low serum B12 level, and this is a readily available screening test in most hospitals.

In folate deficiency, serum folate levels fall prior to RBC folate levels, but by the time most patients present, both serum and RBC folate levels are decreased. Serum folate levels are usually a sufficient assay, but must be drawn prior to transfusion since transfusion raises levels briefly.

Tests for intrinsic factor deficiency:

The Schilling test, the food Schilling test, and the deoxyuridine suppression test all are best undertaken in consultation with a hematologist.

If you are able to confirm that the patient has B12 and folate deficiency anemias, what treatment should be initiated?

B12 can be initially replaced in pediatric patients at a dose of 0.2 ug/kg subcutaneously. For most children, this dose given for 2 days will correct many of the metabolic abnormalities. However complete correction will require daily injections for a week, followed by weekly injections for a month.

Folate at a dose of 1 mg orally daily is usually adequate. In patients with folate deficiency, the diet must be corrected. Goat's milk, which is sometimes used instead of infant formula or cow's milk, is essentially absent of folate. Daily treatment with folate 1mg daily orally is quite adequate for children who do not have intestinal disease. Doses up to 5mg daily may be required for children with absorption problems. Larger doses of folate should be avoided until B12 levels are known, since folate replacement may exacerbate neurologic symptoms in patients with co-existent B12 deficiency.

In cases of severe deficiency, with severe anemia and congestive heart failure, transfusion of PRBC's is indicated. Consultation with both hematologists and gastroenterologists may be needed to determine the underlying cause of the disorder and to guide further therapy.

Disease monitoring and followup

Dietary causes of B12 or folate deficiency must be corrected. GI malasorption may require either B12 injections or unusally large doses of folate. Both hemologic and gastroenterology consultations may be needed.

What is the evidence?

Toh, BH, Ian, R, van Driel, IR, Gleeson, PA. "Pernicious anemia". N Engl J Med. vol. 337. 1997. pp. 1441-8.

Starc, TJ. "Erythrocyte macrocytosis in infants and children with Down syndrome". J Pediatr. 1992. pp. 578-81.

Aslinia, F, Mazza, JJ, Yale, SH. "Megaloblastic anemia and other causes of macrocytosis". Clin Med Res. vol. 4. 2006. pp. 236-41.

Nathan, DG, Ginsburg, D, Orkins, SH. "Megaloblastic anemia". Nathan and Oski's Hematology of infancy and childhood. WB Saunders. 2003. pp. 419.

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