Published on in Children's Doctor
An African-American boy initially was found to have a microcytic anemia with a low hemoglobin of 8.5 g/dL at his 9-month screening. Iron studies revealed a low transferrin saturation of 5 percent and ferritin of 26 ng/mL, consistent with iron deficiency anemia (IDA). He was treated with ferrous sulfate at 2-5 mg/kg/day for a year, but had worsening anemia, prompting referral to Hematology. Further history revealed that he was born at term, received iron-fortified formula until 12 months old then transitioned to 2 to 3 cups of milk per day along with a variety of fruits, vegetables, and meat. He had no history of epistaxis, diarrhea, melena, or hematochezia. His mother reported good adherence with iron therapy. There was no family history of anemia.
Additional work-up included normal hemoglobin electrophoresis, alpha globin gene analysis, lead, and zinc levels. His peripheral blood smear was consistent with IDA with hypochromia, microcytosis, poikilocytosis, and a few pencil forms. An oral iron absorption study showed an inadequate rise in serum iron (from 10 to 25 mcg/dL) one hour after receiving a 3 mg/kg oral dose of iron. Administration of intravenous iron sucrose also was ineffective. Gastroenterology evaluation showed no inflammation or source of bleeding. A bone marrow aspirate and biopsy showed only reduced iron staining. Serum hepcidin assay was elevated consistent with a diagnosis of iron refractory IDA (IRIDA).
Now, at 10 years old, he has persistent microcytic anemia (6.6 to 8.2 g/dL), but he is developing normally without signs or symptoms of IDA.
Iron deficiency is the most common cause of anemia worldwide. In the pediatric population, toddlers and adolescent girls are most commonly affected. In young children, IDA usually is due to inadequate dietary iron intake often coupled with excessive milk consumption, which can also lead to microscopic intestinal bleeding that exacerbates the anemia. Prolonged breast-feeding, without supplemental iron, also predisposes to iron deficiency. Pre-term infants are particularly vulnerable to develop IDA, due to lower iron stores at birth and increased demands from catch-up growth. In contrast, menstrual blood loss coupled with inadequate iron intake in a period of rapid growth places adolescent girls at increased risk of IDA. IDA outside of these risk groups is less common and should prompt investigation for malabsorption or bleeding.
Treatment of IDA includes oral ferrous sulfate at doses of 3 to 6 mg/kg elemental iron daily. With treatment, the reticulocyte count should rise in 3 to 5 days, followed by improvement in the hemoglobin in 7 to 10 days and normalization within 1 month. Lack of improvement most commonly is due to poor adherence with therapy, but alternative causes including malabsorption or ongoing bleeding should also be considered. It is important to assess for side effects of iron therapy, such as constipation, that may impede adherence. Adding fiber or a stool softener, or using alternative oral preparations, may alleviate this problem.
If a treatment response is not seen, an oral iron absorption study should be performed. With this study, the patient comes to the lab fasting. A set of iron studies is drawn, followed by administration of a dose of oral ferrous sulfate (3 to 6 mg/kg), with repeat iron studies at 90 minutes later. In a patient with IDA, the serum iron should rise by at least 50 mcg/dL at 90 minutes. Absent such a response, defects of iron absorption, either intestinal pathology or IRIDA, are likely. If an appropriate rise in the serum iron is evidenced, then adherence should be re-addressed. With adherent patients, consider sources of ongoing bleeding.
IRIDA is a rare cause of iron deficiency due to abnormal hepcidin regulation. Hepcidin is a small peptide produced mainly in the liver. Elevated hepcidin levels inhibit iron absorption from the gut and cause retention of iron in macrophages, limiting the iron available for red cell production, while low hepcidin levels promote iron absorption. To date, all IRIDA cases have been associated with mutations in the TMPRSS6 gene. The product of the TMPRSS6 gene inhibits transcription of hepcidin, so mutations cause inappropriately elevated hepcidin levels (hepcidin levels should be low with IDA).
With IRIDA, there is lifelong, moderate to severe anemia with microcytosis, and hypoferremia. Minimal to no response is seen with oral iron supplementation and there is only a partial response to IV iron administration. Interestingly, clinical signs of IDA tend to be milder with IRIDA, without impairment in growth and development, as was seen in our patient. Treatment involves intermittent parenteral iron administration. In the future, drugs in development that lower hepcidin levels may have clinical benefit.
In summary, IDA is always secondary to an underlying etiology, and it is imperative that a cause is identified. In this case the patient did not have typical risk factors for IDA (full term, formula fed, normal diet) and he did not respond to oral iron therapy as expected. These factors appropriately prompted further evaluation and ultimately a rare disorder diagnosis.
References and suggested readings
Heeney MM, Finberg KE. Iron-refractory iron deficiency anemia (IRIDA). Hematol Oncol Clin N America. 2014;637-652.
Miller, JL. Iron deficiency anemia: A common and curable disease. Cold Spring Harb Perspect Med. 2013;3: a011866.