How I Treat How I treat unexplained refractory iron deficiency anemia

Iron deficiency is one of the most common nutritional problems of the human race. It is associated with serious health risks including abnormal mental and motor development in infancy, impaired work capacity, increased risk of premature delivery, and, in severe anemia, increased maternal and infant mortality. The development of iron deficiency is the consequence of an interaction of 3 distinct risk factors: increased host requirements, limited supply, and increased blood loss. The principles of diagnosis and management in iron deficiency anemia (IDA) are well established and have been defined in a number of detailed guidelines and recommendations. Because increased requirements are the outcome of increased physiologic needs associated with normal development, this category of iron deficiency is often designated physiological or nutritional. By contrast, pathological iron deficiency is most often the result of gastrointestinal disease associated with abnormal blood loss or malabsorption. The intensity of diagnostic efforts to identify underlying pathology depends on the likelihood of encountering such pathology (Figure 1). In subjects with increased requirements and in low-risk patients such as the majority of fertile women, detailed anatomical studies are rarely necessary. By contrast, in grown men and postmenopausal women, the risk of underlying gastrointestinal disease is high and intensive gastrointestinal work up is mandatory. Once the diagnostic procedure is completed, iron deficiency should be treated, preferably by oral medications. However, this general design may fail in several respects: first, conventional endoscopic and radiographic methods are unable to identify the source of gastrointestinal blood loss in a substantial proportion of patients even after using capsule endoscopy. Second, failure to respond to oral iron occurs in a significant proportion of patients regardless of risk category. The prevalence of refractoriness to iron is difficult to define because it is also affected by patient compliance, and the experience and inclination of the physician to use parenteral iron. In the present article, refractoriness to oral iron is defined as failure to respond to treatment at a dose of at least 100 mg of elemental iron per day after 4 to 6 weeks of therapy. Subjects in whom IDA is unresponsive to standard oral iron treatment or in whom anemia persists despite a negative gastrointestinal workup represent an important subgroup of patients referred for hematologic evaluation. Studies in the late 90s have established celiac disease as a possible cause of IDA refractory to oral iron treatment, without other apparent manifestations of malabsorption syndrome. In addition, Helicobacter pylori has been implicated in several earlier studies as a cause of IDA refractory to oral iron treatment, with a favorable response to H pylori eradication. Likewise, autoimmune atrophic gastritis, a condition associated with chronic idiopathic iron deficiency, has been shown to be responsible for refractory IDA in over 20% of patients with no evidence of gastrointestinal blood loss. The availability of convenient, noninvasive screening methods for identifying celiac disease (anti-tissue transglutaminase [TTG] antibodies), autoimmune atrophic gastritis (serum gastrin, parietal cell, or intrinsic factor antibodies), andH pylori infection (antibody screening or fecal antigen and urease breath test), and the recent recognition of rare inherited forms of iron deficiency greatly facilitated the diagnosis of these entities, resulting in an increased awareness of these conditions and their possible role in the causation of IDA. The aim of the present communication is to focus on the role of the above entities in the pathogenesis of refractory IDA, but it is not intended to represent a detailed