Preface

 It is estimated that one-third of the world's population is anemic, the majority being due to iron deficiency (ID). This great health problem affects approximately to more than 2 billion people worldwide, and IDA remains the main cause of anemia, as confirmed by the analy‐ sis of a large number of reports on the burden of disease in near two hundred countries, performed in the last twenty years and by a survey on the burden of anemia in persons at risk, such as preschool children and young women.

 This situation is applied to the reduction of iron stores that precedes to overt iron deficiency anemia (IDA) or persists without progression. This is a more severe condition, in which low levels of iron are associated with anemia and the presence of microcytic hypochromic red cells. The estimated prevalence of ID worldwide, is twice as high the IDA. The diagnosis and treatment of this condition needs clearly to be improved.

 Iron is a metal compound crucial to biologic functions, including respiration, energy produc‐ tion, DNA synthesis, and cell proliferation. The human body has evolved to conserve iron in several ways, including the recycling of iron after the breakdown of red cells and the retention of iron in the absence of an excretion mechanism. However, since excess levels of iron can be toxic, its absorption is limited to 1 to 2 mg daily, and most of the iron needed daily (about 25 mg per day) is provided through recycling by macrophages that phagocytate senescent eryth‐ rocytes. The latter two mechanisms are controlled by the hormone hepcidin, which maintains total-body iron within normal ranges, avoiding both iron deficiency and excess.

 Prevention programs have decreased rates of IDA globally. The prevalence is now highest in Central and West Africa and South Asia. The reported prevalence of ID in the absence of dietary fortification is approximately 40% in preschool children, 30% in menstruating girls and women, and 38% in pregnant women. These rates reflect the increased physiological need for dietary iron during specific life stages according to sex.

 While anemia is clearly defined according to the World Health Organization as a hemoglo‐ bin (Hb) level less than 12 g/dL in women (< 11 g/dL in pregnant women) and lower than 13 g/dL in men, the situation is ambiguous for for iron deficiency. No single test is diagnostic of ID, unless the serum ferritin is low or the percent transferrin saturation is low with an elevated total iron binding capacity

 Iron deficiency anemia (IDA) is a common complication in routine clinical practice that fre‐ quently originates in the gastrointestinal (GI) tract. Patients with IDA are therefore often re‐ ferred to gastroenterologists for further examination and/or treatment. This finding associated with GI disorders can substantially reduces quality of life, contribute to fatigue, and may even lead to hospitalization.

In contrast to the well-documented inflammatory bowel disease (IBD)-associated IDA prev‐ alence data for associated with other pathological conditions of the GI tract, are sparse. Guidelines for the diagnosis and management of anemia and iron deficiency are available for IBD, but not for other GI conditions. Overall, there are three main pathological contribu‐ tors to IDA, namely chronic bleeding, malabsorption and inflammation.-However, otherfac‐ tors, such as poor or selective diet, as well as iron malabsorption (e.g., due to decreased gastric pH) should not be neglected in patients referred for IDA assessment. This applies particularly to elderly patients.

 Celiac disease (CD) is one of the most common chronic inflammatory conditions of the GI system, affecting about 1% of the population. There is a well established relationship be‐ tween CD and IDA. Anemia is the most common presenting symptom of CD, found in 32%-69% of adult patients. Approximately 80% of anemic patients with CD, are also ID. In 49% of anemic patients with CD, ID was found to be the only detectable abnormality. Con‐ versely, among patients presenting with unexplained IDA, 5% have histologically-con‐ firmed CD. Impaired iron absorption (due to villous atrophy of the intestinal mucosa) and blood loss are important pathological contributors to anemia in CD.

 Occult GI bleeding has been detected in about half of patients with CD adhering to a glutenfree diet (GFD). In some patients, nutritional deficiencies may also be a (contributing) causa‐ tive factor. Inflammation is a major contributor to IDA, with interleukin (IL)-1, IL-6, IL-10, interferon (IFN)-γand tumor necrosis factor (TNF)-αas inducers of hepcidin, the main reg‐ ulator of iron homeostasis .

 Accordingly, CD-related IDA, is refractory to oral iron treatment, and even after switching to a GFD, it takes 6-12 mo until most patients recover from anemia. Notably, half of patients remain iron-deficient even after 1-2 years on a GFD. The slow or lacking recovery from ID, may be due to the low absorption rate of nutritional iron (1-2 mg/d), which hinders the re‐ pletion of severely depleted iron stores, and the potentially low content of iron and other micronutrients in a GFD. Therefore, patients with CD clearly benefit from immediate intra‐ venous iron treatment, instead of switching to intravenous iron only after (foreseeable) nonresponse and/or intolerance to oral iron.

 Oral iron is considered the front line therapy, except for conditions such as gastric bypass, heavy uterine bleeding, inflammatory bowel disease, andhereditary hemorrhagic telangiec‐ tasia. Oral iron has many unpleasant side effects, resulting in low patient adherence. For patients intolerant of or unresponsive to, oral iron, intravenous (IV) administration is the preferred route.

 While early formulations were associated with a high incidence of serious adverse events (SAEs), newer formulations are much safer with SAEs occurring very infrequently. Full re‐ placement doses can be administered in a matter of minutes to a few hours. Nevertheless, there remains a reluctance to use IV iron due to a misunderstanding of the safety of the available formulations. Intrevenous iron is safe and effective in all clinical circumstances in‐ cluding pregnancy. The preponderance of published evidence suggests IV iron therapy is underutilized and IV iron should be moved forward in the treatment of ID and IDA.

> **Prof. Luis Rodrigo MD**  Emeritus Full Professor of Medicine University of Oviedo Oviedo, Spain

### **Chapter 1**
