Iron Deficiency

Absolute iron deficiency is defined as low iron stores with or without anemia, whereas iron-deficiency anemia is defined as low hemoglobin due to low iron stores. ^[1] Iron deficiency is the most common micronutrient deficiency worldwide and, when untreated, progresses to anemia. ^{[2] [3]} Absolute iron deficiency affects approximately 2 billion people worldwide and 14% of adults in the US, while iron-deficiency anemia affects approximately 1.2 billion people worldwide. ^[1] Iron deficiency without anaemia is at least twice as common as iron deficiency anaemia, yet it is poorly recognised by clinicians, probably because of suboptimal screening recommendations. ^[4] In high-income countries, approximately 38% of nonpregnant, reproductive-age women have iron deficiency without anemia and about 13% have iron-deficiency anemia. ^[1] Anaemia affects roughly a third of the world's population, and half of these cases are due to iron deficiency. ^[5]

Absolute iron deficiency is caused by increased iron requirements, inadequate iron intake, impaired iron absorption and chronic blood loss. ^[6] The most common causes in adults are menstrual or gastrointestinal bleeding, impaired iron absorption (atrophic gastritis, celiac disease, bariatric surgical procedures), inadequate dietary iron intake and pregnancy. ^[1] According to an American Family Physician review, recurrent blood loss is responsible for 94% of cases of iron deficiency anemia. ^[7] Iron deficiency triggers adaptive changes in cellular iron handling orchestrated by iron regulatory proteins and alterations in systemic iron handling secondary to suppression of the iron regulatory hormone hepcidin. ^[6] Chronic inflammatory conditions are additional risk factors, with reported iron deficiency prevalences of 13% to 90% in inflammatory bowel disease, 24% to 85% in chronic kidney disease, 37% to 61% in heart failure and 18% to 82% in cancer. ^[1] Heavy menstrual bleeding, pregnancy and the postpartum period are the major causes of iron deficiency and iron deficiency anemia in women, in whom both remain underdiagnosed and undertreated.

Individuals with nonanemic iron deficiency or iron-deficiency anemia may be asymptomatic or experience fatigue, difficulty concentrating, exercise intolerance, restless legs syndrome (32% to 40%) and pica (40% to 50%). ^[1] Testing is indicated in patients with anemia or symptoms of iron deficiency and should be considered in those with risk factors such as heavy menstrual bleeding, pregnancy or inflammatory bowel disease. ^[1] A JAMA review diagnoses iron deficiency by a low serum ferritin (typically below 30 ng/mL) in individuals without inflammatory conditions, or by a transferrin saturation below 20%. ^[1] A American Family Physician review uses higher cutoffs: in adults without inflammation, ferritin below 45 ng/mL, or ferritin of 46 to 99 ng/mL with transferrin saturation below 20%, is diagnostic, while in patients with inflammation ferritin below 100 ng/mL is diagnostic. ^[7] In chronic inflammatory conditions, diagnosis is more challenging and requires consideration of higher serum ferritin thresholds and evaluation of transferrin saturation.

Causes of iron deficiency should be identified and treated, and oral iron (ferrous sulfate 325 mg/d or on alternate days) is typically first-line therapy. ^[1] Every-other-day dosing of oral iron improves absorption, and approximately 50% of patients have decreased adherence due to adverse effects. ^[7] In men and postmenopausal women with iron deficiency anemia, bidirectional endoscopy should be performed, and noninvasive testing for Helicobacter pylori infection and celiac disease is recommended. ^[7] Intravenous iron is indicated for oral iron intolerance, poor absorption, chronic inflammatory conditions (chronic kidney disease, heart failure, inflammatory bowel disease, cancer), ongoing blood loss, and the second and third trimesters of pregnancy. ^[1] In a meta-analysis of trials including 7,175 patients with heart failure and iron deficiency, intravenous iron lowered the composite of recurrent heart failure hospitalizations and cardiovascular mortality at 12 months (risk ratio 0.72, 95% CI 0.55 to 0.89). ^[11] Preoperative iron deficiency without anaemia should be corrected to reduce the risk of transfusion and postoperative anaemia.