**6. Initial workup of suspected anemia in children**

In a child with suspected anemia based on history and exam, a minimal workup should be obtained. The goal is to characterize the anemia, and to evaluate the other cell lines (platelets, granulocytes) that define bone marrow function. In most cases a CBC with differential, reticulocyte count, iron panel, ferritin level, and lead level give a strong indication as to the cause and define the therapy.

routes should be considered if the history is not consistent with the more common causes or

A five year old boy presented to his primary care physician with pallor and was found to have a severe microcytic anemia. Stool was negative for occult blood. He was referred to a pediatric hematologist who diagnosed iron deficiency anemia. He had occasional complaints of abdominal pain but no vomiting, diarrhea or constipation. He had not lost any weight but had grown poorly over the past year, falling from the 60th to the 30th percentile for weight and the 50th to the 40th for height. He was referred to a pediatric gastroenterologist, where further studies were done, including an endoscopy showing villous atrophy with increased numbers of intraepithelial lymphocytes consistent with celiac disease. He was placed on a gluten free diet. Three months later his hemoglobin was normal

Although chronic gastrointestinal bleeding is the major cause of severe iron deficiency anemia, there are notable exceptions that involve the GI tract, and lead to severe anemia due to poor iron absorption alone. The model disorders that fit into this category are celiac disease and tropical sprue (Lombardo, 2006). Celiac disease has been shown to be a relatively common cause of anemia in adults, and therefore may be underdiagnosed in children; it is increasingly recognized as presenting with a spectrum of severity (Van Heel, 2005). Genetics play a strong role in susceptibility but the full genetic pattern is incompletely

Iron absorption may also be disrupted when substantial segments of bowel, particularly the proximal duodenum, are removed surgically. Intractable inflammatory bowel disease, traumatic abdominal injury, and structural defects such as intestinal volvulus or intussusception, as well as necrotizing enterocolitis and typhlitis may necessitate intestinal resection, leading to a defect in iron absorption that may take years to manifest clinically. There are also rare gastrointestinal disorders leading to either malabsorption of iron or chronic blood loss or both, such as collagenous gastritis (Suskind et al., 2009), epidermolysis

To the general practitioner however, it is enough to remember that unless dysfunctional uterine bleeding is elicited from the history, or for any male or prepubertal female, the cause of any *severe, acquired severely microcytic* anemia must be gastrointestinal, which should

In a child with suspected anemia based on history and exam, a minimal workup should be obtained. The goal is to characterize the anemia, and to evaluate the other cell lines (platelets, granulocytes) that define bone marrow function. In most cases a CBC with differential, reticulocyte count, iron panel, ferritin level, and lead level give a strong

if the patient does not respond adequately to therapy.

and his weight had increased to the 50th percentile.

bullosa (Fridge & Vichinsky, 1998) and short gut syndromes.

**6. Initial workup of suspected anemia in children** 

indication as to the cause and define the therapy.

**5.2 Celiac disease (Case 7)** 

**5.2.1 Discussion** 

understood.

guide the appropriate referral.

In general, the more cell lines that are depressed, and the lower the values, the more likely is an underlying marrow disease. Hence, pancytopenia (neutropenia, anemia, and thrombocytopenia) makes leukemia more likely while an isolated single cytopenia (neutropenia, anemia, *or* thrombocytopenia) makes a peripheral disorder outside the marrow more likely. If leukemia or a primary marrow failure is suspected, referral to a pediatric hematologist/oncologist should be made promptly for further testing, including a marrow evaluation. An isolated severe microcytic anemia is not consistent with leukemia and indicates slow blood (i.e. iron) loss (gastrointestinal or vaginal), or in the case of celiac disease, lack of iron absorption. The severe depletion of iron leads to marrow failure in a sense, in that the marrow is unable to complete heme synthesis. Despite the marrow "failure," further marrow evaluation of marrow function is not part of the evaluation, as the underlying cause is entirely outside the marrow.

In iron deficiency anemia a clue to otherwise normal marrow function is often provided by a "left shift" of the other cell lines; leukocytosis, elevated neutrophil count, increased bands and other immature forms, and an elevated platelet count with large platelets. The reticulocyte count is often only mildly elevated, reflecting the lack of iron substrate. Hemolytic anemias such as sickle cell disease, autoimmune hemolytic anemia and hereditary spherocytosis also shift cell lines to the left, but are not microcytic and present with a much higher reticulocyte count. A high reticulocyte count makes a hemolytic anemia likely, especially if the anemia is normocytic or mildly macrocytic. B12 and folate deficiency are not microcytic and are considerably rarer than iron deficiency. The iron panel is usually consistent with other studies, but serum iron may be misleading, as recent ingestion of iron may elevate the value. Ferritin, as an acute phase reactant, may also be elevated in a deficiency state, but low values always represent iron deficiency, and occur in no other condition. A lead level should be considered, not as a cause of microcytic anemia, but because of its association with iron deficiency due to pica and increased lead absorption, especially in small children.

Children, especially the very young tolerate chronic anemia extremely well. It is not unusual for a toddler with a hemoglobin well below five to act perfectly normal, with the very slow onset of pallor as the only manifestation of the anemia. Some fussiness and irritability might be noticed in retrospect. Often these children appear yellow due to underlying normal pigments. True jaundice can be ruled out if the sclerae are white, and lab evaluation of liver function is therefore not necessary. Hepatosplenomegaly is unusual, as is true decompensation e.g. heart failure, but shortness of breath on exertion and headache are common in older children and young adults.

#### **7. Therapy of iron deficiency anemia**

The therapy of iron deficiency anemia is strongly guided by the cause. Iron therapy is only part of the treatment. For mild anemias due to previous iron loss that has resolved, oral iron is all that is required. If bleeding is ongoing, iron may partially correct the anemia without affecting the underlying cause, leading to delay in diagnosis and therapy of the underlying cause. The most egregious example is the adult with colon cancer; Iron therapy alone would allow the cancer to progress without diagnosis.

Transfusions are usually not required, especially in children, but should be considered in cases of decompensation or heart failure. It is said that transfusions for chronic anemia in

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children are given because of the elevated heart rate of the doctor, rather than the patient. If used, packed red cells should be given slowly under the direction of a pediatric hematologist or other experienced clinician to avoid the risk of fluid overload due to the hyperdynamic state of chronic severe anemia.

Response to therapy depends on the disorder, the severity of the deficiency and compliance, not only with the prescribed iron, but in removing the bleeding source. Especially in children whose bleeding is due to excess whole milk, the response to oral iron will be slow or nonexistent if the milk intake is not severely cut back or eliminated from the diet. Intake of acid foods such as orange juice aid iron absorption, and hypochorhydric states, such as produced by proton pump inhibitors, has been reported to impair absorption (Sharma et al., 2004). The amount of iron in typical vitamin supplements (about 10 mg of elemental iron daily), while sufficient to prevent deficiency, is well below the 3-6 mg *per kg* required as treatment. If compliant with therapy, the hemoglobin should rise by 1 g/dL or more during the first week, along with an increased reticulocyte count, and the hemoglobin should be nearly normal by 4-6 weeks. Iron therapy should be continued for several weeks beyond normalization of the hemoglobin, as pointed out previously, in order to replenish iron stores in the body.
