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Treatment of Iron Deficiency in Gastroenterology: a New Paradigm

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Treatment of Iron Deficiency in Gastroenterology: a New Paradigm NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #194 Carol Rees Parrish, MS, RDN, Series Editor Treatment of Iron Deficiency in Gastroenterology: A New Paradigm Michael Auerbach Brian W. Behm Abhinav Sankineni Iron deficiency is the most common micronutrient deficiency in the world and complicates a host of gastrointestinal maladies associated with blood loss. Oral iron, the frontline standard, is often poorly tolerated and ineffective. Oral iron may also cause injury to gastrointestinal epithelium and has been shown to negatively impact the gut microbiome. Newer formulations of intravenous iron have been to shown to be effective with a similar safely profile to placebo. These formulations contain complex carbohydrates that bind elemental iron more tightly, allowing a complete replacement dose to be administered in a single office visit of 15-60 minutes. Total dose infusion of intravenous iron improves convenience for both physician and patient and decreases the overall cost of care. There is now ample evidence to move intravenous iron to the frontline in all gastrointestinal disorders in which oral iron is ineffective, and should be the preferred route of administration when oral iron intolerance occurs. INTRODUCTION ron deficiency is recognized as the most common these areas are at high risk for iron deficiency. micronutrient deficiency, estimated to affect Bleeding is a common manifestation of many GI Imore than 35% of the world’s population.1 Cells disorders, and subsequently iron deficiency, with with the greatest ability to absorb iron are found in or without anemia, is a frequent comorbidity. the distal duodenum and proximal jejunum. Patients with GI disease or surgical resections affecting Iron Absorption Iron, in the presence of gastric acid, is conjugated Michael Auerbach, MD, FACP* Auerbach to vitamin C, amino acids, and sugars, which Hematology and Oncology Baltimore, MD Clinical protect it from the alkaline secretions of the Professor of Medicine Georgetown University pancreas, which are necessary for normal digestion. School of Medicine Washington, DC Brian W. Absent that event, the iron is converted to ferric Behm MD, MS Associate Professor of Medicine hydroxide (rust), which is unabsorbable from the Division of Gastroenterology University of Virginia GI tract. Dietary iron is best taken on an empty Charlottesville, VA Abhinav Sankineni MD, MPH stomach, which allows the gastric acid to promote Co-Director Interventional Gastroenterology MedStar binding, and is then absorbed in the duodenum and Franklin Square Hospital Center Baltimore, MD *Data management funding from AMAG Pharmaceuticals (continued on page 20) 18 PRACTICAL GASTROENTEROLOGY • JANUARY 2020 Treatment of Iron Deficiency in Gastroenterology: A New Paradigm NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #194 (continued from page 18) Table 1. GI Conditions Commonly proximal jejunum. Iron homoeostasis is regulated Associated with Iron Deficiency by the protein hepcidin, which has a crucial role in iron availability to tissues by blocking both • Erosive esophagitis/gastritis absorption at the level of the intestinal epithelium • Peptic ulcer disease and iron release from circulating macrophages. This regulation is mediated by hepcidin’s ability • Gastrointestinal angiodysplasia to irreversibly inactivate ferroportin-1 (FPN1), the • Gastrointestinal malignancy 2 only known iron export protein in humans. The • Inflammatory bowel disease due to: inactivation of ferroportin by hepcidin results in o Inflammation in the small bowel decreased absorption and subsequent failure of with malabsorption the intracellular iron to be loaded on to transferrin for subsequent erythropoiesis. Circulating o Chronic blood loss macrophages, a reservoir for iron, are similarly Chronic inflammatory state expressed with ferroportin with similar loss of the o function of iron export in the presence of hepcidin. • Celiac disease Helicobacter pylori Subsequently, high expression of hepcidin (due to • Helicobacter pylori inflammation and other co-morbid conditions, oral iron supplementation, iron sufficiency) decreases • Gastric bypass, or any other surgery plasma iron concentrations; low expression (due where the duodenum and proximal to iron deficiency, hemochromatosis) increases jejunum are bypassed plasma iron concentrations. • Atrophic gastritis Disease States Altering Iron Absorption A number of frequently occurring GI disorders stores are depleted. As a result, iron deficiency is may impair iron absorption (Table 1). Helicobacter often present without anemia, but may result in pylori may cause iron malabsorption by causing symptoms of fatigue, decreased exercise tolerance, atrophic gastritis, resulting in reduced soluble iron pagophagia (ice craving), or other forms of pica, for absorption from acid insufficiency.3 Long term and restless leg syndrome. use of high dose proton pump inhibitors (PPIs) and autoimmune atrophic gastritis may also contribute ORAL IRON SUPPLEMENTATION to iron deficiency through a similar mechanism.4,5 It was in 1681 when Sydenham first used iron After roux en y gastric bypass, the blind loop filings in cold wine to treat the symptoms of (consisting of distal stomach, duodenum and the ‘green sickness’,12 later termed chlorosis by proximal jejunum) is bypassed. As a result, oral Pierre Blaud. It was not long thereafter that oral iron is not available for absorption, precipitating iron was used to treat patients with wounds during iron deficiency in the majority of patients despite the American Civil war. Today, iron deficiency is oral supplementation.6 Patients with gastric bypass the most common micronutrient deficiency on the may also have diet alterations as well as a reduction planet, and oral iron remains frontline therapy for in gastric acid, both of which contribute to iron most conditions. The advantages of oral iron are deficiency.7,8 Celiac disease can cause duodenal that it is readily available, inexpensive, convenient, inflammation resulting in iron malabsorption and noninvasive. Unfortunately, significant GI side and resulting deficiency.9 Iron deficiency with effects frequently occur, which often leads to poor inflammatory bowel disease (IBD), in addition to adherence. A recent meta-analysis of prospective bleeding, is exacerbated by inflammation in the studies comparing oral ferrous sulfate to placebo small bowel with malabsorption and the chronic and parenteral iron found more than 70% of inflammatory state associated with the disease.10,11 patients reported significant GI toxicity with oral Early on, dietary iron may provide enough iron to iron, including nausea, abdominal pain, diarrhea, maintain normal hemoglobin concentrations as iron and constipation.14 20 PRACTICAL GASTROENTEROLOGY • JANUARY 2020 Treatment of Iron Deficiency in Gastroenterology: A New Paradigm NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #194 While several oral iron preparations have Table 2. Common Oral Iron Preparations been marketed with claims of superiority in either ¨ Carbonyl iron (iron pentacarbonyl) tolerability or efficacy, none have been shown in prospective studies to be superior to ferrous ¨ Ferric citrate sulfate15,16 (Table 2). Oral formulations with slow release of iron and those with enteric coating ¨ Ferric maltol * may result in better GI tolerance, but are released ¨ Ferrous ascorbate beyond the duodenum and proximal jejunum (primary site for iron absorption). This results in ¨ Ferrous chloride** a lack of adequate GI absorption, and thus these ¨ Ferrous fumarate formulations should not be prescribed due to their lack of clinical efficacy.15 Studies have shown that ¨ Ferrous gluconate oral dosing of iron upregulates hepcidin levels, leading to impairment of intestinal iron absorption.17 ¨ Ferrous succinate** Absorption of oral iron tablets decreases when ¨ Ferrous sulfate taken daily or twice daily, compared to alternate day therapy,18 thus alternate day dosing of oral iron ¨ Ferrous sulfate anhydrous may be a preferable dosing regimen. ¨ Polysaccharide-iron complex Inflammatory Bowel Disease Although oral iron is commonly prescribed to * Approved by FDA July 2019 treat iron deficiency in patients with IBD, several ** Not routinely available in US studies have shown it is not appropriate in the Patients with GI motility disorders and small setting of active disease. Oral iron has been shown intestinal bacterial overgrowth have symptoms of to exacerbate intestinal inflammation of IBD bloating, abdominal discomfort and altered bowel independent of anemia,19 and cause luminal changes habits.24 As a result, this population also does not in microbiota and bacterial metabolism, which may tolerate oral iron well. Finally, strong evidence negatively alter the microbiome.20,21 Studies have supports avoidance of oral iron after gastric bypass also found response to oral iron therapy depends and with ongoing active blood loss.15,25 on levels of C-reactive protein (CRP), with high CRP levels correlating with weaker hemoglobin INTRAVENOUS IRON response.22 Thus, iron should only be given orally In the past, many clinicians were taught that to IBD patients with inactive disease, mild anemia, intravenous iron was dangerous; much of this and good tolerance of oral iron; in patients with misperception stems from the early use of colloidal active IBD oral iron should be avoided. One new ferric hydroxide and high molecular weight iron oral iron formulation, ferric maltol, has been dextran, both of which were associated with toxicity studied in patients with inactive
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