Symptom-Based Diagnosis in Pediatrics (CHOP Morning Report) 1st Ed.

CASE 2-1

Fifteen-Year-Old Girl

PHILLIP SPANDORFER

HISTORY OF PRESENT ILLNESS

A 15-year-old girl presented to the emergency department with a 3-month history of increasing fatigue. She gradually stopped participating in sports because of dizziness and palpitations. Her decreased level of activity has worsened to the point that as soon as she returns home from school in the afternoon she sleeps the rest of the day. She has had an 18-pound weight loss during this time period. Furthermore, for the past 5 days she has had a headache and occasional nonbloody, nonbilious

MEDICAL HISTORY

She was the product of a full-term delivery and has had no major medical illnesses. She has not required any surgeries. emesis. For the past 4 days she has also had mild upper abdominal pain. The remainder of her history and review of systems were noncontributory.

PHYSICAL EXAMINATION

T 37.2°C; HR 110 bpm; RR 16/min; BP 100/60 mmHg

Weight and Height 25th percentile

On examination she appeared pale and tired, but was nontoxic appearing. She answered questions appropriately. Her head and neck examination revealed pale conjunctiva. She did not have any papilledema. Her lungs were clear to auscultation. Cardiac examination revealed tachycardia, but there were no murmurs or other abnormal heart sounds. Her abdomen was soft with normal bowel sounds. There was no hepatosplenomegaly. Capillary refill was delayed at 3 seconds. Her neurologic examination was normal. Of particular interest is the fact that her cranial nerve examination and motor strength were also normal.

DIAGNOSTIC STUDIES

A complete blood count revealed a white blood cell count of 2100 cells/mm3 (3% bands, 45% segmented neutrophils, 51% lymphocytes), hemoglobin of 5.4 g/dL, and a platelet count of 173 000/mm3. The mean corpuscular volume (MCV) was elevated at 98.7 fL.

COURSE OF ILLNESS

The patient was hospitalized for evaluation of her severe anemia. The peripheral blood smear provided a clue to the diagnosis (Figure 2-1).

Image

FIGURE 2-1 Peripheral blood smear. (Photo courtesy of Marybeth Helfrich, MT, ASCP).

DISCUSSION CASE 2-1

DIFFERENTIAL DIAGNOSIS

The patient has a significant anemia. Anemia can be categorized on the basis of several etiologies. It could be because of nutritional deficiencies such as iron, folic acid, or vitamin B12. It could also be because of hemoglobinopathy, such as sickle cell anemia or thalassemia. The anemia could be from a hemolytic process such as hereditary spherocytosis or glucose-6-phosphatedehydrogenase deficiency. Finally, anemia could be from a hypoplastic or aplastic crisis.

When evaluating anemia, it is easiest to arrive at the correct diagnosis by assessing the hematologic indices, specifically the MCV. If the MCV is low, anemia is a microcytic anemia and causes iron deficiency anemia, lead poisoning, anemia of chronic disease, and thalassemias should be considered. If the MCV is normal, chronic disease, hypoplastic or aplastic crisis, malignancy, renal failure, acute hemorrhage, and hemolytic processes should be considered. Finally, if the MCV is high, the megaloblastic anemias should be evaluated, specifically folate deficiency, vitamin B12 deficiency, as well as some of the aplastic anemias.

DIAGNOSIS

Returning to our patient, we see that she had a macrocytic anemia as indicated by an elevated MCV of 98.7 fL. A hypersegmented neutrophil is located in the center of the peripheral blood smear (Figure 2-1). In the lower portion of the figure are several megaloblasts with a loose-appearing nuclear chromatin. Also noted are numerous misshapen mature erythrocytes, reflecting the mechanical fragility associated with megaloblastic anemias (Figure 2-1). The appropriate next step would be to measure the folate levels and vitamin B12 levels in her serum. Her folate levels returned at 8.2 ng/mL with normal in the range of 2-20 ng/mL. Her vitamin B12 level was less than 100 pg/mL with normal levels ranging from 200 to 1100 pg/mL. On further questioning, the patient stated that she has been a strict vegan for the past two years and has had no meat or animal-based products. Additionally, she did not take vitamin supplements and did not attempt to eat nonmeat-based foods containing vitamin B12, such as fortified cereal and fortified meat analogues (e.g., wheat gluten, soy-products). The diagnosis is dietary vitamin B12 deficiency.

INCIDENCE AND EPIDEMIOLOGY

Dietary vitamin B12 must combine with a glyco-protein (intrinsic factor) that is secreted from the gastric fundus. The vitamin B12-intrinsic factor complex is then absorbed at the terminal ileum via specific receptor mechanisms. Vitamin B12 is present in many foods and a pure dietary deficiency is rare. However, it may be seen in patients who do not drink any milk or eat eggs or animal products (vegans). Vitamin B12 deficiency can also result from lack of secretion of intrinsic factor in the stomach. When the cause of the lack of intrinsic factor is chronic atrophic gastritis, this condition is referred to as pernicious anemia. Other causes of vitamin B12 deficiency include surgical resection of the terminal ileum, regional enteritis of the terminal ileum, overgrowth of intestinal bacteria, disruption of the B12-intrinsic factor complex, abnormalities/absence of the receptor site in the terminal ileum, or inborn errors of the metabolism of vitamin B12.

CLINICAL PRESENTATION

Vitamin B12 plays an important role as a cofactor for two metabolic reactions, methylation of homocysteine to methionine and conversion of methylmalonyl coenzyme A to succinyl CoA. Vitamin B12deficiency leads to accumulation of these precursors. Methionine is an important step in the synthesis of DNA. RNA production and cytoplasmic components are produced normally and the red blood cell production in the bone marrow yields large cells and hence a macrocytic anemia. Methionine is also converted to S-adenosylmethionine, which is used in methylation reactions in the central nervous system and hence CNS effects are seen with vitamin B12 deficiency. Neurologic manifestations in children include abnormalities, such as paresthesias, loss of developmental milestones, hypotonia, seizures, dementia, and depression. The neurologic changes are not always reversible.

DIAGNOSTIC APPROACH

Complete blood count and folic acid and vitamin B 12levels. The term megaloblastic anemia refers to a macrocytic anemia usually accompanied by a mild leukopenia or thrombocytopenia. The presence of a macrocytic anemia with normal folic acid levels and low vitamin B12 levels will diagnose most vitamin B12 deficiencies. However, reliance on abnormal hemoglobin may miss up to 30% of adult cases of vitamin B12 deficiency. On peripheral blood smear there are numerous schistocytes and misshapen mature red blood cells due to the increased mechanical red blood cell fragility associated with this condition. Erythroid precursors have loose appearing chromatin, giving them a characteristic appearance. Hypersegmented or multilobar neutrophils may also be noted. The appearance of at least one neutrophil with more than six lobes or more than five neutrophils with more than five lobes is considered significant. To assist in the diagnosis of vitamin B12 deficiency, serum levels of homocysteine and methylmalonyl coenzyme A may be elevated. Levels of methylmalonic acid (MMA), a precursor to methylmalonyl coenzyme A, may be elevated as well.

Other studies. After the diagnosis of vitamin B12 deficiency has been made, further studies can be performed to identify the cause. Specifically, a comprehensive dietary assessment, evaluation for parasitic infections, Schilling test (measures ability to absorb orally ingested vitamin B12), amino acid analysis, measurement of the unsaturated B12 binding capacity and transcobalamin II levels, genetic evaluation, and measurement of antibodies to parietal cells and intrinsic factor. Subspecialty consultation is often required to assist with the diagnosis.

TREATMENT

Treatment of vitamin B12 deficiency depends on the cause. Frequently, vitamin B12 administration is necessary. If the anemia is severe, treatment should be instituted slowly and in a monitored environment. For malabsorptive causes, long-term treatment will be indicated. The recommended treatment is monthly injections of 100 μg/d of vitamin B12. Following the clinical response and laboratory values enables the clinician to titrate treatment to the patient’s response. It is not known whether folic acid therapy in patients who have vitamin B12 deficiency will worsen the neurologic symptoms of the vitamin B12deficiency and may mask the hemato-logic symptoms of the megaloblastic anemia. In this case, the patient received a vitamin B12 injection and then began oral multivitamin and vitamin B12 supplementation. She also received nutritional counseling to help her create a nutritionally balanced vegan diet.

SUGGESTED READINGS

1. O’Grady LF. The megaloblastic anemias. In: Keopke JA, ed. Laboratory Hematology. New York: Churchill Livingstone; 1984:71-83.

2. Rasmussen SA, Fernhoff PM, Scanlon KS. Vitamin B12 deficiency in children and adolescents. J Pediatr. 2001;138:10-17.

3. Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician. Arch Intern Med. 1999;159:1289-1298.

4. Toh BH, van Driel IR, Gleeson PA. Pernicious anemia. N Engl J Med. 1997;337:1441-1448.

5. Whitehead VM, Rosenblatt DS, Cooper BA. Megaloblastic anemia. In: Nathan DG, Orkin SA, eds. Nathan and Oski’s Hematology of Infancy and Childhood. 5th ed. Philadelphia: W.B. Saunders Company; 1998: 385-422.