Case Files Pediatrics, (LANGE Case Files) 4th Ed.


A 2-year-old girl, born at 32 weeks’ gestation, comes to your clinic for an initial visit. Her 1-month stay in the neonatal intensive care unit was complicated by necrotizing enterocolitis (NEC), requiring surgical removal of a small section of her intestine that included the ileocecal valve. She had an uncomplicated postoperative course, and her mother declares she has been developing normally and gaining weight. She has a healthy appetite, a varied diet, and no history of abnormal stooling. Her mother is concerned, though, that she has been getting progressively paler since her last clinic visit with another provider 6 months ago. Physical examination reveals an overall healthy-appearing toddler with normal vital signs. She has pallorous skin and conjunctivae and a well-healed abdominal surgical scar. The remainder of her physical examination is normal. You order a complete blood count (CBC) and a reticulocyte count and find that the hemoglobin is 7 g/dL, the mean corpuscular volume is 110 fL, and the reticulocyte count is 2%.

Image What is the most likely cause of this child’s anemia?

Image How should she be treated?


Macrocytic (Megaloblastic) Anemia Secondary to Vitamin B12 Deficiency

Summary: A 2-year-old former premature infant with history of NEC and intestinal resection presenting with pallor and anemia.

• Most likely cause: Vitamin B12 deficiency secondary to terminal ileal resection and compromised intestinal absorption.

• Treatment: Monthly intramuscular vitamin B12 supplementation.



1. Describe the typical findings in macrocytic anemia.

2. List the potential causes of macrocytic anemia.

3. Understand the treatment options for macrocytic anemia.


Evaluation of a child with suspected anemia involves performing thorough personal and family histories and a comprehensive physical examination. Anemia can result from a variety of disorders, including defective red blood cell production, hemolysis, or blood loss. The clinician’s goal, therefore, is to gather historical clues (atypical patient or family dietary histories, family history of blood dyscrasias) and examination findings (splenomegaly, flow murmur, hematochezia) that are important in guiding appropriate diagnostic and therapeutic plans.


Macrocytic Anemia


MEAN CORPUSCULAR VOLUME (MCV): Average size of a red blood cell; large cells are macrocytic; small cells are microcytic.

RETICULOCYTE COUNT: Percentage of red blood cells that are immature (new).

INTRINSIC FACTOR: Glycoprotein secreted in the stomach that binds to vitamin B12; the intrinsic factor–vitamin B12 complex then attaches to receptors in the distal ileum and is absorbed.


Anemia typically is distinguished by the size of the red blood cells. Children with iron deficiency develop a microcytic anemia and typically have a low MCV;their red blood cells are smaller than normal because of the decreased amount of hemoglobin in each cell. Children who quickly lose a large amount of blood usually have a normocytic anemia; the cells are normal, but there are fewer of them.

Various conditions may result in macrocytic anemia, usually associated with an elevated MCV. Hypothyroidism, trisomy 21, vitamin B12 deficiency, and folate deficiency often are associated with macrocytic anemia and a low reticulocyte count, as a result of inadequate bone marrow production. A macrocytic anemia also may be seen with active hemolysis, but usually this anemia is accompanied by an elevated reticulocyte count.

Vitamin B12-mediated macrocytic anemia can occur as a result of dietary deficiency, malabsorption, or inborn errors of metabolism. Vitamin B12, an important factor in DNA synthesis, is available in many foods (meats, fish, eggs). A pure dietary deficiency is rare in children, but diets devoid of all animal products may result in a deficiency. Breast-fed infants of mothers who adhere to a strict vegan diet are at risk for vitamin B12 deficiency.Malabsorption can occur when the terminal ileum is absent, as in this case scenario, or when infectious or inflammatory conditions compromise intestinal function.

Children with the rare condition “juvenile pernicious anemia” are unable to secrete intrinsic factor and become vitamin B12 deficient between the ages of 1 and 2 years, when the supply of vitamin B12 passed transplacentally from mother to child is exhausted. These children will exhibit worsening irritability, loss of appetite, and decreased activity. Children affected with this condition are at risk for permanent neurologic damage resulting from spinal cord demyelinization. Therapy is intramuscular vitamin B12 replacement. High-dose oral replacement may be corrective (limited, inconclusive studies at present) in patients with intrinsic factor deficiency or severe dietary deficiency that cannot be corrected with dietary modification.

A variety of other more unusual causes of vitamin B12 deficiency can be listed. The fish tapeworm Diphyllobothrium latum uses vitamin B12, and intestinal infestation can result in macrocytic anemia. Similarly, any intestinal infectious or inflammatory process, such as parasitic infection or inflammatory bowel disease, could promote vitamin B12 deficiency. Infants exclusively fed on goat’s milk, nutritionally deficient in both vitamin B12 and folate, are at risk not only for vitamin B12 deficiency but also brucellosis if the milk is unpasteurized. For infants fed on goat’s milk, vitamin and mineral supplementation is required.

Treatment for B12 deficiency is guided by the underlying disorder. Eradicating or suppressing a gastrointestinal infection or inflammatory disorder should promote sufficient mucosal repair to permit adequate vitamin B12absorption, and further vitamin B12 therapy may not be required. For patients with an inability to produce intrinsic factor and for those with absence or permanent dysfunction of the gastric antrum or terminal ileum (the site of intrinsic factor production and absorption, respectively) monthly parenteral vitamin B12 therapy is indicated.

For patients with macrocytosis but normal B12 and folate levels, consideration for atypical bone marrow pathology (such as leukemia or myelodysplasia) must be entertained. Referral to a pediatric hematologist would be warranted.


27.1 You are called to the bedside of a mother who just delivered a healthy term infant and has a question regarding her infant’s nutrition. The mother was fed goat’s milk as a child and wants to do the same for her infant. Under which of the following conditions is goat’s milk acceptable as infant nutrition?

A. Goat’s milk proteins are hydrolyzed before feeds.

B. Infants are provided supplemental vitamins and minerals.

C. Goat’s milk is freshly obtained from goats.

D. Infants of mothers with milk intolerance should preferentially receive goat’s milk.

E. Goat’s milk is diluted with water.

27.2 You receive the results of a CBC you performed in your clinic on a pallorous 9-month-old boy. Other than pallor, no historical or physical examination concerns were noted during the patient’s visit. The laboratory technician reports a hemoglobin of 8.6 g/dL, an MCV of 105 fL, and platelet count of 98,000/mm3. You are also told that the white blood cell count is 8500/mm3 and the differential reveals 47% neutrophils and 42% lymphocytes, and that no atypical lymphocytes are seen. Which of the following is the most appropriate next step in this child’s care?

A. Measure serum iron and total iron binding capacity levels.

B. Begin oral iron supplementation.

C. Measure vitamin B12 and folate levels.

D. Begin oral vitamin B12 and folate supplementation.

E. Obtain a stat referral to pediatric hematologist.

27.3 The parents of a previously healthy 3-year-old girl bring the child to your clinic because she is complaining that her tongue hurts. The parents also report that she has appeared weak and listless over the last several months, and has not been eating well. Recently she has exhibited trouble walking. The family usually eats a regular diet, including meats and vegetables. On physical examination, she is pale and tachycardic. Her complete blood count reveals a macrocytic anemia. You suspect a vitamin or mineral deficiency. What additional finding is most likely in this toddler?

A. Red tongue

B. Petechiae and ecchymoses

C. Muscle fasciculation

D. Hair loss

E. Blue sclerae

27.4 You are working at a Native American clinic in Alaska. A 16-year-old adolescent female comes to your clinic for an evaluation of lethargy. Her father notes that recently she has looked pale. She eats a regular diet and has no significant past medical history. Her menses are regular and have not been excessive. During the last few years, she has helped her mother in the family seafood restaurant after school, but is increasingly tired and unable to complete all of her work. Her CBC reveals a megaloblastic anemia. Which of the following is the next appropriate study?

A. Folate level

B. Stool for rotavirus

C. Iron level

D. Stool for ova and parasites

E. Transcobalamin level


27.1 B. Infants drinking goat’s milk must have nutritional supplementation with vitamin B12, folate, and iron. Several goat’s milk–based formulas including these nutrients are available. Fresh, unpasteurized goat’s milk can contain Brucella ovis and cause brucellosis. Diluting milk will only serve to dilute the caloric content.

27.2 C. This infant has hematologic parameters consistent with macrocytic anemia. The mild thrombocytopenia reported is periodically seen in patients with vitamin B12 deficiency, and is thought to be related to impaired DNA synthesis and ineffective thrombopoiesis. The results reported are not typical for iron deficiency, and neither an iron panel nor iron supplementation is warranted. At this point, your workup should include checking folate and B12levels; supplementation of these compounds is not yet justified. Myelodysplasia or leukemia is in the differential, but is probably less likely with a normal white blood cell count and differential (no atypical cells); referral to pediatric hematology may ultimately be required, but some preliminary data can be gathered first.

27.3 A. A smooth, red, and tender tongue may be observed in juvenile pernicious anemia, a rare autosomal recessive condition in which the child is not able to secrete intrinsic factor and cannot absorb vitamin B12. Supplies of vitamin B12 passed to the fetus from the mother typically are sufficient for at least the first 1 to 2 years of life. A deficiency in transcobalamin results in megaloblastic anemia in infancy because transcobalamin is required for B12transport and utilization; therefore, vitamin B12provided by the mother cannot be used effectively. Petechiae may occur with vitamin C or K deficiency, muscle fasciculation with vitamin D and calcium disturbance, and hair loss with zinc deficiency.

27.4 D. The fish tapeworm Diphyllobothrium latum uses vitamin B12 for growth and egg production; as many as one million eggs per day may be produced. The parasite also inactivates the vitamin B12–intrinsic factor complex, inhibiting absorption in the terminal ileum. The fish tapeworm is the longest tapeworm to infect humans, sometimes growing to more than 10 m in length. Most infestations are asymptomatic, with megaloblastic anemia occurring in 2% to 9% of tapeworm infections. Risk factors include eating raw or undercooked fish. In North America, it is most commonly seen in the northern United States, Alaska, and Canada. Eggs have a unique morphology and are easily found in stool samples.


Image Vitamin B12 dietary deficiency is rare; infants breast-fed by vegan mothers are at risk to become vitamin B12 deficient and should receive supplementation.

Image Infants drinking goat’s milk must be supplemented with vitamin B12, folate, and iron.

Image Vitamin B12 deficiency related to gastric antrum or ileal resection requires parenteral vitamin B12supplementation.

Image Vitamin B12 deficiency can lead to permanent neurologic damage.


Blanton R. Adult tapeworm infections. In: Kliegman RM, Stanton BF, St. Geme JW, Schor NF, Behrman RE, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: WB Saunders; 2011:1232-1234.

Journeycake JM, Yang J, Chan AKC. Normal and abnormal hemostasis. In: Rudolph CD, Rudolph AM, Lister GE, First LR, Gerson AA, eds. Rudolph’s Pediatrics. 22nd ed. New York, NY: McGraw-Hill; 2011: 1569.

Lerner NB. Megaloblastic anemias. In: Kliegman RM, Stanton BF, St. Geme JW, Schor NF, Behrman RE, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: WB Saunders; 2011:1655.

Martin PL. Nutritional anemias. In: McMillan JA, Feigin RD, DeAngelis CD, Warshaw JB, eds. Oski’s Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:1692-1696.