Version July 2025
INTRODUCTION —
Determining the cause of iron deficiency is an essential component of management, regardless of whether the individual has iron deficiency anemia or iron deficiency without anemia.
This topic discusses causes of iron deficiency and the approach to determining the cause, which is an essential part of management.
Separate topics discuss:
●Diagnosis
•Children – (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis".)
•Adolescents – (See "Iron requirements and iron deficiency in adolescents", section on 'Evaluation and presumptive diagnosis'.)
•Adults – (See "Diagnosis of iron deficiency and iron deficiency anemia in adults".)
•Pregnancy – (See "Anemia in pregnancy", section on 'Screening during pregnancy' and "Anemia in pregnancy", section on 'Evaluation of anemia'.)
●Treatment
•Children – (See "Iron deficiency in infants and children <12 years: Treatment".)
•Adolescents – (See "Iron requirements and iron deficiency in adolescents", section on 'Management'.)
•Adults – (See "Treatment of iron deficiency anemia in adults".)
•Pregnancy – (See "Anemia in pregnancy", section on 'Treatment of iron deficiency'.)
●Physiology of iron absorption and trafficking – (See "Regulation of iron balance".)
IMPORTANCE OF DETERMINING THE CAUSE —
Iron deficiency refers to low iron stores. Severe iron deficiency causes anemia. (See "Diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Stages of iron deficiency'.)
A finding of iron deficiency, with or without anemia, indicates that another condition is causing reduced iron stores and should be identified [1]. There are many possible causes. (See 'Causes (organized by mechanism)' below.)
It is important to determine the cause for the following reasons:
●Underlying conditions may require treatment – The underlying condition leading to iron deficiency may require additional interventions and treatments, such as gluten avoidance for celiac disease or surgery for colorectal or gastric cancer. Several of the common causes of blood loss, such as colonic and uterine cancer, have ominous prognoses unless discovered and treated promptly. (See 'Treatment of the underlying condition and follow-up' below.)
●Iron deficiency may persist or recur – If the cause is not determined, it may contribute to an inadequate response to treatment or recurrence of iron deficiency following treatment. (See "Treatment of iron deficiency anemia in adults", section on 'Response to iron supplementation'.)
●Risk factor awareness – Awareness of risk factors is critical for:
•Patient education – Educating patients about possible symptoms and risk factors can facilitate appropriate seeking of medical assistance if iron deficiency recurs.
•Guiding the medical history and examination – Directed questions for the patient history and directed physical examination can be used to assess for subtle symptoms of iron deficiency that may not be reported or signs and symptoms that the individual may not associate with iron deficiency, such as pica, hair loss, or restless legs syndrome. (See 'History' below and "Diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Clinical manifestations'.)
•Determining whether to screen – Individuals at high risk for iron deficiency are candidates for screening. (See "Diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Screening (asymptomatic individuals)' and "Anemia in pregnancy", section on 'Screening for anemia and iron deficiency'.)
CAUSES (ORGANIZED BY MECHANISM)
Overview of causes — Iron deficiency may be caused by blood loss, decreased iron absorption, and/or decreased dietary intake.
The table provides an overview of causes and risk factors for iron deficiency (table 1); these are discussed in the sections below. (See 'Blood loss' below and 'Decreased iron absorption' below and 'Causes of reduced dietary intake' below.)
In adults in resource-abundant settings, dietary intake is almost always adequate, and it is usually reasonable to assume that the cause is blood loss until proven otherwise, with the implied need to search for and identify the cause. (See 'Evaluation for the cause' below.)
Blood loss — Blood loss is the major cause of iron deficiency in adults and adolescents living in resource-rich settings (table 1); it can be overt or occult [2-7].
Sources of blood loss — Gastrointestinal (GI) and gynecologic bleeding are common causes of blood loss.
Overt bleeding is obvious and not difficult for the clinician to recognize, often by history alone:
●Heavy menstrual bleeding
●Traumatic hemorrhage
●Major surgery with significant blood loss
●Hematemesis or melena
●Hemoptysis
●Pregnancy and delivery
●Hematuria
For heavy menstrual bleeding, the quantity of bleeding (frequency of changing pads, duration of menses) should be specifically queried, as some individuals may have been told that the amount of bleeding is normal when in fact it is excessive. The table provides guidance to making this determination (table 2). Underestimation of the degree of heavy menstrual bleeding is especially relevant in kindreds with hereditary bleeding disorders such as von Willebrand disease, because relatives may consider heavy bleeding to be normal since it is similar to what they have experienced or witnessed. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'Heavy menstrual bleeding'.)
Other causes of blood loss that may be overlooked include:
●Occult bleeding, typically GI in etiology, including gastritis, malignancy, telangiectasias, or angiodysplasia
●Hemodialysis
●Hemolysis with urinary iron losses
●Frequent or recurrent blood donation
●High-intensity athletics or military training, with iron loss through sweat, GI bleeding, traumatic hemolysis, and other causes
●GI parasites (hookworm, whipworm), especially in parts of the world with favorable soil conditions for growth
●Excessive diagnostic blood testing, although this would require extensive daily phlebotomy and is unlikely to cause iron deficiency in an individual with adequate baseline iron stores [8]
Details are presented below.
Typical magnitude of blood loss/iron loss in selected conditions — Typical body iron stores are 5 to 10 mg/kg, with the lower values more common in premenopausal females and higher values in males and postmenopausal females [9,10].
The amount of iron lost per mL of blood loss is approximately 0.5 mg (equivalent to 50 mg iron loss per 100 mL of blood loss). Losing 50 mg of iron is unlikely to cause iron deficiency in most individuals, although it may be a contributing factor in individuals with borderline stores. Even occasional blood donors (approximately 225 to 250 mg iron lost per donation) are often able to rebuild stores between donations. However, chronic ongoing losses over months to years by any mechanism will eventually deplete iron stores.
●Occult GI bleeding – The likelihood that iron deficiency is due to an occult GI tumor has been illustrated in several case series:
•In a 2012 series of 621 patients with definite or probable iron deficiency anemia, of whom 301 underwent upper or lower endoscopy, cancer and high-risk adenomas were identified in 51 (16 percent) [11]. Detection of a lesion on endoscopy did not correlate with results of stool guaiac testing.
•In a 2005 series of 148 adults (median age, 66 years) with chronic iron deficiency anemia who underwent endoscopy, 18 (12 percent) had a malignant tumor [12].
•In a 2002 report from the first National Health and Nutrition Examination Survey and Epidemiologic Follow-up Study (NHANES I) that included 9024 adults, 18 new GI malignancies were identified [13]. Iron deficiency was a strong predictor of GI cancer in males and postmenopausal but not premenopausal females, with the following rates of GI cancer detection over a two-year period:
-Premenopausal females with iron deficiency – 0 of 442
-Males and postmenopausal females with iron deficiency – 5 of 274 (2 percent)
-Males and postmenopausal females without iron deficiency – 11 of 5733 (0.2 percent)
●Pregnancy – Typical iron loss has been estimated at approximately 1000 mg for pregnancy (including delivery). (See "Anemia in pregnancy", section on 'Iron deficiency'.)
●Menstrual blood loss – Menstrual blood losses usually account for approximately 0.5 to 5 mg of iron loss per day of menses or 25 mg per cycle [14].
●Hemodialysis – Typical iron loss during hemodialysis may be as much as 2000 mg per year, which is highly likely to produce iron deficiency without supplementation. (See "Diagnosis of iron deficiency in chronic kidney disease" and "Treatment of iron deficiency in patients on dialysis".)
●Blood donation – Each unit of donated whole blood contains approximately 225 to 250 mg of iron in 450 to 500 mL of blood. Donating a unit of blood is unlikely to cause iron deficiency in an individual with adequate iron stores, but iron deficiency may develop in regular blood donors, especially those who donate frequently. The prevalence of iron deficiency in blood donors is discussed separately. (See "Blood donor screening: Overview of recipient and donor protections", section on 'Iron deficiency without anemia'.)
●Urinary or pulmonary hemosiderosis – In some conditions, iron may be lost when there is bleeding into a tissue such as the lungs or kidneys, iron scavenging, and shedding of iron-laden cells, especially over a prolonged period of time or multiple episodes.
•Urinary – Chronic or intermittent intravascular hemolysis with hemosiderin accumulation in urinary epithelial cells may lead to iron loss through urinary shedding of these cells. Examples include individuals with intensive athletic training, prosthetic heart valve-associated hemolysis, or paroxysmal nocturnal hemoglobinuria (PNH). (See "Overview of the management of patients with prosthetic heart valves", section on 'Hemolytic anemia' and "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Hemolysis'.)
•Pulmonary – Pulmonary hemosiderosis, such as in individuals with diffuse alveolar hemorrhage or idiopathic pulmonary hemosiderosis may lead to iron loss through iron-laden alveolar or bronchial epithelial cells. These conditions also may cause a component of functional iron deficiency, in which iron is trapped in pulmonary macrophages. (See "Idiopathic pulmonary hemosiderosis" and "The diffuse alveolar hemorrhage syndromes".)
Decreased iron absorption — Reduced iron absorption despite adequate intake from diet has several possible causes.
Abnormal absorptive surfaces — Iron is absorbed in the upper GI tract; the duodenum is the site of maximal absorption [15]. Several factors determine the efficiency of iron absorption, and certain medical conditions may interfere with normal absorption of dietary iron (table 1).
The most clinically important are conditions that affect the mucosal cells responsible for iron absorption, such as:
●Atrophic (autoimmune) gastritis, celiac disease, and/or Helicobacter pylori infection (see 'Atrophic gastritis/celiac disease/H. pylori' below)
●Bariatric surgery (see 'Bariatric surgery' below)
●Medications that reduce gastric acid, such as proton pump inhibitors, histamine 2 receptor blockers, and antacids (see 'Medications' below)
●Inherited disorders that interfere with iron absorption (very rare) (see 'Inherited disorders/IRIDA' below)
Sources of reduced iron absorption may be considered in individuals with GI symptoms or those who do not have an adequate response to oral iron supplementation. (See "Treatment of iron deficiency anemia in adults", section on 'Response to iron supplementation'.)
Regardless of whether reduced iron absorption is documented, it may be important to also consider and evaluate for a possible source of bleeding. (See 'Evaluation for the cause' below.)
Atrophic gastritis/celiac disease/H. pylori — These are relatively common conditions affecting the mucosal cells responsible for iron absorption in the upper GI tract [16,17]. These conditions may be more common than previously appreciated.
●Autoimmune gastritis – In one series of 373 individuals with iron deficiency (nearly all premenopausal females, and approximately half of whom had anemia), 69 (18 percent) had anti-parietal cell antibodies [18]. Of the subset of 26 with anti-parietal cell antibodies who underwent upper endoscopy, 12 had a histologic diagnosis of autoimmune gastritis confirmed. Histologic diagnosis correlated with higher antibody levels (>100 units/mL); none of the individuals with antibody levels <20 units/mL who had endoscopy for other reasons were found to have gastritis. In a series of 150 patients (mostly adults) with iron deficiency anemia, refractoriness to oral iron treatment was noted in 24 of 34 (71 percent) with anti-parietal cell antibodies and autoimmune gastritis [19]. (See "Metaplastic (chronic) atrophic gastritis", section on 'Autoimmune metaplastic atrophic gastritis'.)
Anti-parietal cell antibodies can also interfere with vitamin B12 absorption and cause vitamin B12 deficiency. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Pernicious anemia'.)
●Celiac disease – In celiac disease, small bowel inflammation is triggered by exposure to gluten in susceptible individuals. Celiac disease predominantly affects White individuals of northern European ancestry, with a prevalence of approximately 1 in 70 to 1 in 300 (0.3 to 1.4 percent). The prevalence is higher in first-degree relatives of an individual with celiac disease. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults".)
Celiac disease can contribute to iron deficiency by several mechanisms, including reduced absorption of iron, chronic inflammation with increased hepcidin, and blood loss, although the contribution (if any) of GI blood loss from celiac disease to iron deficiency is unclear [20]. Malabsorption of other nutrients required for red blood cell (RBC) production including vitamin B12, folic acid, and copper may cause or exacerbate anemia [20].
Various reports have commented on the unexpected finding of celiac disease in individuals with iron deficiency and vice versa. As an example, in a series of 102 patients diagnosed with celiac disease in a northern European hospital, 70 (69 percent) had anemia as the presenting feature, and 34 of these 70 (approximately one-half) were premenopausal females who might otherwise be thought to have iron deficiency on the basis of heavy menses [21]. In another series of 200 Scandinavian patients with anemia who underwent testing for celiac disease, 10 (5 percent) were found to be positive by serologic testing and confirmed by intestinal biopsy [22].
●H. pylori – In a series of 373 individuals with iron deficiency, 24 of 167 (14 percent) screened positive for H. pylori antigen in stool [18]. In a series of 71 patients with iron deficiency with anemia, who did not have an obvious source of blood loss and underwent upper and lower endoscopy, 13 (18 percent) were diagnosed with H. pylori [5].
Refractoriness to oral iron treatment may be seen in both autoimmune and H. pylori-related gastritis. In a series of 150 patients (mostly adults) with iron deficiency anemia, refractoriness to oral iron treatment was noted in 24 of 34 (71 percent) with anti-parietal cell antibodies and autoimmune gastritis and in 15 of 22 (68 percent) with H. pylori (as well as all eight with celiac disease) [19].
The possibility of these conditions should be reviewed and testing obtained in individuals with unexplained iron deficiency, especially those at increased risk based on demographic features and those for whom oral iron therapy is ineffective. (See 'Evaluation for the cause' below and "Treatment of iron deficiency anemia in adults", section on 'Approaches to lack of response'.)
Bariatric surgery — Iron must be conjugated to vitamin C, amino acids, or sugars in the presence of gastric acid; otherwise, the alkaline secretions in the proximal jejunum will convert the iron to ferric hydroxide (rust), which is unabsorbable. Bariatric surgery removes or bypasses gastric mucosa where acid is produced as well as jejunal mucosa where iron is normally absorbed.
Bariatric procedures that bypass the duodenum such as roux-en-Y gastric bypass (RYGB) and biliopancreatic diversion with duodenal switch (BPD-DS) have the greatest risk of causing iron deficiency because they reduce the site of maximal absorption and in some cases reduce gastric acidity. (See "Bariatric procedures for the management of severe obesity: Descriptions" and "Regulation of iron balance", section on 'Intestinal iron absorption'.)
Routine iron supplementation and monitoring of iron status are used after most bariatric surgeries. Other nutrients required for RBC production also require supplementation. (See "Bariatric surgery: Postoperative nutritional management".)
Medications
●Reduced gastric acidity – An acidic gastric environment facilitates absorption of iron (especially non-heme iron, from plant sources). Medications that reduce gastric acidity, especially proton pump inhibitors (PPIs), have been proposed to reduce iron absorption from foods and iron supplements. This is mainly based on observational studies that suggest a dose-response relationship between the dose of PPI (or duration of use) and risk of iron deficiency [23-26].
However, medication-induced reduced gastric acidity alone is unlikely to cause clinically significant iron deficiency in individuals with adequate dietary iron intake and a normally functioning GI tract. Further, these studies may indicate association rather than causation; individuals taking a PPI are more likely to have GI conditions that lead to bleeding or reduced iron absorption, such as those listed above. (See 'Sources of blood loss' above and 'Atrophic gastritis/celiac disease/H. pylori' above.)
If an individual with iron deficiency is taking a PPI, antacid, or histamine receptor blocker, we do not attribute iron deficiency to the medication without performing an evaluation for bleeding or reduced iron absorption as indicated for the individual. We take the opportunity to re-evaluate whether the PPI is actually indicated, and we review the symptoms that led to PPI use and make sure they are properly evaluated. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders".)
●Increased risk for GI bleeding – Medications that cause gastritis and/or increase the risk of GI bleeding may cause iron deficiency. These include nonsteroidal antiinflammatory drugs (NSAIDs), aspirin, and anticoagulants. However, we do not attribute iron deficiency to these medications without also evaluating the underlying source of bleeding. (See 'Blood loss' above.)
Gastric protection to reduce the risk of upper GI bleeding in individuals on chronic antithrombotic therapies is presented separately. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Gastric protection'.)
Diet — Dietary iron exists as heme iron (from meat) and non-heme iron (from plant sources and fortified cereals). Heme iron is better absorbed, but both are important sources of dietary iron.
Causes of reduced dietary intake — Reduced dietary intake is rarely responsible for iron deficiency in adolescents and adults in resource-abundant settings. However, resource-limited settings and certain dietary practices may be associated with reduced iron intake that may cause (rare) or contribute to iron deficiency, especially in individuals with additional risk factors.
The main causes of reduced iron intake include:
●Resource-limited settings – Iron deficiency in resource-limited settings is usually multifactorial. In addition to insufficient dietary iron, other causes include excessive iron loss during pregnancy, and increased risk of helminthic infections causing GI blood loss [27].
●Vegetarian/vegan and other diets – A review of studies evaluating iron deficiency in individuals who follow a vegetarian or vegan diet found they were more likely to be iron deficient than individuals who follow an omnivorous diet [28]. While non-heme iron is available from a wide array of vegetables and supplemented grains and cereals, the bioavailability of non-heme iron is lower, and some diets may not contain sufficient iron for some individuals, especially those with menstrual and/or pregnancy-related iron loss [29].
The recommended daily allowance of iron and iron contents of foods (table 3) are discussed separately.
●Adolescents – (See "Iron requirements and iron deficiency in adolescents", section on 'Iron requirements'.)
●Adults – (See "Overview of dietary trace elements", section on 'Iron'.)
●Pregnancy – (See "Nutrition in pregnancy: Dietary requirements and supplements", section on 'Iron'.)
Foods that affect iron absorption
●Foods that reduce iron absorption – A number of foods may impair iron absorption (table 4):
•Tannates (found in tea and red wine)
•Phosphates
•Phytates (mineral-binding compounds found in whole grains and seeds)
•Foods high in calcium
However, iron deficiency should not be attributed to these foods without a thorough evaluation. (See 'Evaluation for the cause' below.)
●Foods that increase iron absorption – Vitamin C creates an acidic gastric environment and may increase iron absorption, as discussed separately. (See "Treatment of iron deficiency anemia in adults", section on 'Interventions to enhance absorption'.)
It would be difficult to develop iron deficiency solely due to a diet high in tannates, phosphates, phytates, or calcium or to prevent iron deficiency by taking vitamin C. However, eating foods that interfere with absorption may contribute to iron deficiency in individuals with ongoing blood loss, or, less commonly, extremely low intake [7].
A case report described iron deficiency in an individual who drank excessive amounts of tea (more than 1500 mL daily for 20 years) [30]. Upper and lower endoscopies were negative, and hemoglobin was documented to increase with cessation of tea drinking and to decrease when tea drinking was resumed.
Paradoxically, pica (ingestion of non-food substances), which is a symptom of iron deficiency, can also worsen iron absorption, depending on the substance ingested. (See "Diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Pica and ice craving'.)
Special scenarios
Pregnancy — Pregnancy is associated with very high prevalence of iron deficiency, often progressing to iron deficiency anemia. Causes, screening, and evaluation are discussed separately. (See "Anemia in pregnancy", section on 'Iron deficiency' and "Anemia in pregnancy", section on 'Screening during pregnancy' and "Anemia in pregnancy", section on 'Evaluation of anemia'.)
Redistribution after EPO/erythropoiesis-stimulating agents (ESAs) — Treatment with erythropoietin (EPO) for the anemia of chronic kidney disease (CKD) often leads to the discovery of absolute or functional iron deficiency (also called anemia of chronic disease/anemia of inflammation [ACD/AI]). (See "Diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Absolute versus functional deficiency'.)
This is particularly a problem in individuals undergoing maintenance hemodialysis. Individuals undergoing hemodialysis may lose an average of 2000 mg of iron per year, mainly from repeated blood testing and blood losses within the hemodialysis circuit [31]. This, combined with EPO, which mobilizes iron for RBC production, causes iron deficiency in almost all patients undergoing dialysis who are treated with EPO, as well as some individuals with CKD who are not undergoing dialysis, unless supplemental iron is administered. This subject is discussed separately. (See "Treatment of iron deficiency in patients with nondialysis chronic kidney disease (CKD)" and "Treatment of iron deficiency in patients on dialysis" and "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease".)
EPO or other erythropoiesis-stimulating agents (ESAs) are also used for patients with cancer-associated anemia. The anemia may be multifactorial and include a component of bleeding and iron deficiency. Functional iron deficiency due to increased hepcidin, the primary mediator of ACD/AI, may limit the availability of iron and the response to ESA therapy in these patients, and those with borderline iron stores may rapidly develop iron deficiency. Iron status is routinely monitored, and supplementation often provided, as discussed separately. (See "Role of ESAs in adults with non-hematologic cancers" and "Causes of anemia in patients with cancer".)
High-intensity athletics — Iron deficiency may be seen in some athletes and is not uncommon in runners [32]. (See "Diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Epidemiology'.)
Mechanisms include [33-37]:
●Reduced iron intake
●GI blood loss
●Iron loss in sweat (0.6 mg per liter)
●Traumatic hemolysis
Other causes of anemia may also contribute, as discussed separately. (See "Overtraining syndrome in athletes", section on 'Anemia and iron deficiency'.)
Inherited disorders/IRIDA
●IRIDA due to pathogenic variants in the TMPRSS6 gene – Iron refractory iron deficiency anemia (IRIDA) is a rare inherited (autosomal recessive) disorder in which absorption of oral iron is markedly impaired due to increased hepcidin levels. The genetics and pathophysiology are discussed separately. (See "Regulation of iron balance", section on 'Hemojuvelin'.)
In published case reports as well as our own experience, patients with IRIDA are not anemic at birth, and the clinical phenotype develops after approximately one month of age. Suspicion for IRIDA usually occurs during a pediatric routine evaluation. (See "Screening tests in children and adolescents", section on 'Iron deficiency'.)
However, in some patients, the condition is recognized only in adulthood, either because the anemia is mild or because it has been misclassified. Patients present with mild hypochromic, microcytic anemia with very low iron stores. Serum ferritin levels are mostly within the normal range or even slightly elevated following treatment with intravenous iron, but transferrin saturation (TSAT) is low [38]. (See "Diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Iron studies (list of available tests)'.)
The diagnosis is pursued after elimination of causes of iron deficiency refractory to iron therapy such as celiac disease, H. pylori infection, autoimmune gastritis, or ACD/AI [39]. Diagnostic confirmation requires demonstrating biallelic pathogenic variants in TMPRSS6; testing laboratories are listed on the Genetic Testing Registry website (GTR).
●Pathogenic variants in the SLC11A2 gene– Iron deficiency anemia has also been described in individuals with pathogenic variants in the SLC11A2 gene, which encodes the divalent metal transporter DMT1 [40-44]. (See "Regulation of iron balance", section on 'Divalent metal transporter 1 and duodenal cytochrome b'.)
EVALUATION FOR THE CAUSE —
Identifying and treating the cause of iron deficiency is an essential part of management, along with repleting iron stores. This is true regardless of the severity of the deficiency and/or the presence of anemia [45,46]. (See "Iron requirements and iron deficiency in adolescents", section on 'Management' and "Treatment of iron deficiency anemia in adults".)
In resource-abundant settings, iron deficiency is likely to be due to blood loss (table 1). Even in resource-limited settings, iron deficiency should not be attributed to dietary deficiency without appropriate consideration and investigation of possible blood loss.
History — Causes of iron deficiency differ depending on patient age, menstrual and pregnancy history, and specific symptoms or risk factors that brought the individual to medical attention. Individuals with suspected iron deficiency should be asked about symptoms, medical and surgical history, prior gastrointestinal evaluation, dietary practices, and medications, especially if there is not a history of known bleeding or malabsorption. Family history may also indicate a possible condition that increases risk.
●Symptoms – In addition to questions used in the diagnosis of iron deficiency (pica/pagophagia, restless legs syndrome), the following should be queried to help determine the cause:
•In females, menstrual, pregnancy, and lactation history. Heavy menstrual bleeding (table 2) should specifically be queried, with details that indicate the amount of blood loss. (See 'Sources of blood loss' above and 'Pregnancy' above.)
•Symptoms of gastrointestinal (GI) bleeding (melena, hematemesis, coffee-ground emesis, and black/tarry stools).
•GI symptoms that might suggest celiac disease, autoimmune gastritis, or H. pylori infection (dyspepsia, abdominal discomfort, diarrhea, steatorrhea).
•Weight loss, which could be a sign of cancer, a condition causing malabsorption or anorexia, or other chronic inflammatory condition.
•Symptoms of bleeding from another site (especially postmenopausal uterine bleeding; other rare examples include hematuria or hemoptysis).
●Medical and surgical history – Relevant considerations include a history of:
•Chronic kidney disease, especially requiring hemodialysis or an erythropoiesis-stimulating agent
•Surgical procedure with significant blood loss
•Bariatric surgery (See 'Bariatric surgery' above.)
•Celiac disease
•Colorectal cancer
•Other GI disorder
•Bleeding disorder
•Regular blood donor
●Prior GI and gynecologic evaluations – Results of previous endoscopies and other GI testing, as well as gynecologic evaluations should be reviewed. (See 'Sources of blood loss' above.)
Repeat endoscopic evaluation may be required, even if previous endoscopies were negative. (See 'Indications for endoscopic evaluation' below.)
●Medications – Antithrombotic medications, including aspirin, other nonsteroidal antiinflammatory drugs (NSAIDS), and anticoagulants may increase the risk of bleeding. NSAIDs can also cause peptic ulcer disease and small bowel enteropathy [47]. Use of aspirin and/or over-the-counter NSAIDs should be queried specifically. However, iron deficiency should not be attributed to these medications without identifying a source of bleeding or malabsorption. (See 'Medications' above.)
Certain medications interfere with iron absorption by decreasing gastric acidity. Use of a proton pump inhibitor (PPI) or histamine receptor antagonist should be queried, including over-the-counter formulations. However, iron deficiency should not be attributed to these medications without identifying a source of bleeding or malabsorption.
Current or previous use of (or requirement for) iron supplementation is worth asking to determine if iron deficiency is new or recurrent.
●Dietary practices and exercise – Dietary practices that decrease iron absorption (excessive tea drinking or calcium intake) and high intensity athletics (marathon running, military training) should be assessed. (See 'Diet' above and 'High-intensity athletics' above.)
●Family history – Conditions with a hereditary component may include:
•Colorectal cancer syndromes (or colorectal cancer in individuals <40 to 45 years).
•Celiac disease.
•Bleeding disorders such as von Willebrand disease (VWD), hemophilia, platelet disorder, or hereditary hemorrhagic telangiectasia (HHT).
•History of requiring blood transfusions or need for iron supplements may indicate an undiagnosed bleeding disorder.
Patients with overt bleeding source — If an overt source of bleeding is identified (melena, hematochezia, heavy menstrual bleeding, gross hematuria, recent surgery with blood loss), we first focus on further evaluation and treatment of the blood loss as appropriate, in addition to treating the iron deficiency. In patients with GI bleeding or other GI symptoms, this may warrant up-front endoscopy. Endoscopy is especially important in individuals with GI bleeding who are over age 40, regardless of the frequency of symptoms or magnitude of blood loss. (See "Approach to acute upper gastrointestinal bleeding in adults" and "Approach to acute lower gastrointestinal bleeding in adults".)
In patients in whom a bleeding source is identified and treated and who have resolution of iron deficiency after iron repletion, we do not necessarily pursue further work-up unless they develop new signs or symptoms, if iron deficiency recurs without explanation, or if indicated based on age-appropriate colorectal cancer screening. If iron deficiency recurs, we then consider further work-up as below.
Indications for endoscopic evaluation — As above, individuals with overt GI bleeding require endoscopy to evaluate the source, with the choice between initial upper endoscopy and colonoscopy guided by the specific bleeding symptoms. (See 'Patients with overt bleeding source' above.)
In patients who do not have overt bleeding or symptoms (or those with iron deficiency unresponsive to treatment), a key question is whether GI endoscopic evaluation is warranted to evaluate for malignancy, and upper GI conditions that interfere with iron absorption such as H. pylori, autoimmune gastritis, celiac disease, or other pathologies.
Role of serologies before endoscopy — Individuals with upper GI symptoms may additionally warrant serologic evaluation (eg, for atrophic gastritis or celiac disease) prior to endoscopy. For example, in individuals with nausea and diarrhea after eating gluten-containing foods, serologic testing informs the endoscopic approach to biopsies. (See "Diagnosis of celiac disease in adults" and "Metaplastic (chronic) atrophic gastritis", section on 'Laboratory testing'.)
Males and non-menstruating females — The likelihood of a GI source of blood loss is higher in males and non-menstruating females than in other populations. Consistent with guidelines from the European Hematology association (EHA) and other organizations, we test for a source of GI bleeding in these individuals [45,48,49]. The specific test(s) and sequence of testing depends on patient symptoms, values and preferences, and available resources.
In males and non-menstruating females with iron deficiency (with or without anemia) without another obvious cause (see 'Causes (organized by mechanism)' above), we refer to gastroenterology for bidirectional (upper and lower) endoscopy [48,49]. There may be exceptions, such as endurance athletes who have iron deficiency without anemia and are <40 years old. (See 'Iron deficiency without anemia' below.)
We do not limit the evaluation to postmenopausal females or individuals with GI symptoms, because even premenopausal females and people who do not report GI symptoms may have a GI source. A negative history of blood in the stool or negative fecal occult blood testing also should not be used to eliminate the possibility of a GI source of bleeding, since bleeding may be intermittent and/or too small of an amount to turn the stool dark (and the sensitivity of fecal testing for occult blood is relatively low). (See "Tests for screening for colorectal cancer", section on 'Fecal immunochemical test (FIT) for blood'.)
An exception to pursuing endoscopies might be an older individual who would prefer not to be evaluated or treated for malignancy. (See "Evaluation of occult gastrointestinal bleeding", section on 'Evaluation of isolated iron deficiency anemia'.)
Oral iron may interfere with the colon preparation for colonoscopy and should be avoided before the procedure [45]. (See "Overview of colonoscopy in adults", section on 'Medications'.)
Menstruating females — In many cases, iron deficiency anemia may be due to menstrual losses or recent pregnancy, and GI endoscopy may not be needed, especially in younger individuals (eg, <40 years).
However, certain features favor endoscopic evaluation, including GI symptoms (eg, bowel changes, weight loss), persistent iron deficiency despite treatment of the etiology of heavy menses (table 2), age ≥40 years, or a positive family history of early colorectal cancer or a colorectal cancer syndrome. (See "Evaluation of occult gastrointestinal bleeding", section on 'Premenopausal female patients'.)
For example, if a 43 year old female patient with iron deficiency and heavy menses due to uterine fibroids is treated with uterine artery embolization, with resolution of heavy menses, and iron deficiency persists following a course of iron therapy, endoscopic evaluation may be appropriate.
Iron deficiency without anemia — Guidelines and expert opinion are less clear on the role of endoscopy in otherwise asymptomatic patients with iron deficiency without anemia (also called non-anemic iron deficiency) [48-50].
Consistent with some guidelines, we refer to gastroenterology for endoscopy in patients with non-anemic iron deficiency who are 40 to 45 years or older, those with elevated risk for colorectal cancer, and those with no explanation for iron deficiency. An exception may be an individual with low life expectancy and/or comorbidities that would prohibit treatment if a bleeding source is found.
In patients <40 years with non-anemic iron deficiency, we perform individualized risk-benefit assessment and discuss the lower risk of a missed GI pathology (including malignancy and atrophic gastritis) versus the small risks of endoscopy, and we use shared decision making in deciding which patients to refer for endoscopy. As an example, we may not pursue endoscopy in a young, otherwise healthy and asymptomatic individual, particularly if iron deficiency was discovered as part of surveillance due to other risk factors (eg, heavy menstrual bleeding, recent pregnancy, high intensity athletics, hereditary hemorrhagic telangiectasia).
Overall, the likelihood of gastrointestinal malignancy in individuals with non-anemic iron deficiency appears to be lower than in those with iron deficiency anemia (though risk is still elevated compared with non-iron deficient, non-anemic individuals) [13,49].
In one prospective cohort study of over 9000 participants that recorded GI cancer diagnoses over a two-year period [13]:
●Among males and postmenopausal females, diagnosis rates for GI malignancy were:
•Non-iron deficient, non-anemic individuals – 11 of 5733 (0.2 percent)
•Iron deficient individuals without anemia – 2 of 223 (1 percent; relative risk [RR] 5, 95% CI 1-21)
•Iron deficient individuals with anemia – 3 of 51 (6 percent; relative risk 31, 95% CI 9-107)
●Among 442 premenopausal females with iron deficiency (92 with anemia and 350 without anemia), none were diagnosed with a GI malignancy.
Direct evidence on the likelihood that endoscopy will detect cancer in an individual with iron deficiency without anemia is limited. One case control study of adults with iron deficiency with or without anemia (mean age 60 years) who underwent endoscopy showed lower rates of GI malignancy detected in those without anemia (1.8 percent, versus 14.2 percent in those with anemia) [51]. Other diagnoses besides malignancies included gastritis, angiodysplasias, and polyps.
Patients over the age of 45 years, regardless of whether they have iron deficiency or anemia, may warrant colonoscopy as part of routine colorectal cancer screening, as discussed separately. (See "Screening for colorectal cancer: Strategies in patients at average risk".)
Individuals for whom the cause is not readily found — In some patients who have undergone initial serologies and/or endoscopies, a source of iron deficiency may not be identified. In these individuals, we assess whether the initial endoscopic evaluation was adequate (eg, effective colonoscopy preparation). If not, repeat endoscopy may be necessary.
If a source of iron deficiency has not been identified and appropriate GI evaluations have been performed as detailed above, it may be reasonable to attribute iron deficiency to causes such as CKD, hemodialysis, frequent blood donation, bariatric surgery, or other non-GI, non-gynecologic causes as appropriate. Clinical judgment is required to determine whether further evaluation is needed, considering the patient's age, overall clinical presentation, monitoring over time, and response to iron repletion. Individuals who develop new iron deficiency or increased iron requirements after bariatric surgery may warrant evaluation for a new cause of iron deficiency; additional testing is based on symptoms.
Further evaluation for small bowel bleeding may be pursued in some patients and is presented in detail separately. We do not always pursue small bowel bleeding sources if there are other possible non-GI sources of iron deficiency and no specific reasons to suspect small bowel bleeding. The need for an evaluation for small bowel bleeding is typically assessed in consultation with a gastroenterologist. (See "Evaluation of suspected small bowel bleeding (formerly obscure gastrointestinal bleeding)".)
Ongoing monitoring and vigilance for response to treatment and recurrence of iron deficiency can assist in deciding whether repeat or further investigation is needed.
Referral to hematology or a genetics expert to evaluate rare genetic disorders may be appropriate in selected individuals with refractory iron deficiency, especially if relatives share the phenotype. (See 'Inherited disorders/IRIDA' above.)
TREATMENT OF THE UNDERLYING CONDITION AND FOLLOW-UP —
Treatment of the condition causing iron deficiency is an important component of management when possible.
Follow-up for conditions causing iron deficiency depends on the condition identified. Chronic conditions generally require periodic monitoring, while causes that have resolved may not require additional monitoring or testing unless symptoms recur.
Details are presented in separate topic reviews:
●GI bleeding – (See "Approach to acute upper gastrointestinal bleeding in adults" and "Approach to acute lower gastrointestinal bleeding in adults".)
●Gastritis – (See "Metaplastic (chronic) atrophic gastritis".)
●Celiac disease – (See "Management of celiac disease in children" and "Management of celiac disease in adults".)
●Heavy menstrual bleeding – (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management".)
●Pregnancy – (See "Anemia in pregnancy", section on 'Postpartum'.)
Iron stores generally require reassessment after a treatment course has been completed. Individuals for whom the underlying condition is treated (institution of a gluten-free diet, removal of a colonic or uterine polyp) may have periodic re-checking of iron stores, with the interval extended if stores remain adequate. These individuals should have a low threshold for retesting if symptoms of either iron deficiency or the underlying condition recur. (See "Treatment of iron deficiency anemia in adults", section on 'Response to iron supplementation'.)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anemia in adults" and "Society guideline links: Pediatric iron deficiency".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Low iron (The Basics)")
●Beyond the Basics topics (see "Patient education: Anemia caused by low iron in adults (Beyond the Basics)")
PATIENT PERSPECTIVE TOPIC —
Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Iron deficiency anemia".)
SUMMARY AND RECOMMENDATIONS
●Diagnosis of iron deficiency – The prevalence and diagnostic evaluation for iron deficiency are discussed separately. (See "Iron requirements and iron deficiency in adolescents" and "Diagnosis of iron deficiency and iron deficiency anemia in adults" and "Anemia in pregnancy", section on 'Iron deficiency'.)
●Overview of causes – Iron deficiency may be caused by blood loss, decreased iron absorption, and/or decreased dietary intake (table 1). In adults in resource-abundant countries, dietary intake is almost always adequate, and it is usually reasonable to assume that the cause is blood loss until proven otherwise. Risk factor awareness is critical for patient education. Individuals at high risk are candidates for screening and should have a very low threshold for evaluating symptoms, no matter how subtle. (See 'Causes (organized by mechanism)' above.)
•Blood loss – Gastrointestinal (GI) and gynecologic sources are common sources of blood loss. Overt bleeding is obvious and not difficult for the clinician to recognize, often by history alone. For heavy menstrual bleeding, the quantity of bleeding (frequency of changing pads, duration of menses) should be specifically queried, as some individuals may have been told that the amount of bleeding is normal when in fact it is excessive. Other causes of blood loss and the typical magnitude of iron loss are listed above. Anticoagulants and antiplatelet agents may increase bleeding, but bleeding should not be attributed to these medications without identifying the bleeding site. (See 'Blood loss' above and 'Medications' above.)
•Decreased absorption – Iron is absorbed in the upper GI tract, especially the duodenum. Absorption requires an acidic environment. Causes of decreased absorption include bariatric or other upper GI surgery, atrophic gastritis, celiac disease, and Helicobacter pylori. Acid-reducing medications or certain dietary practices may interfere with absorption but alone are unlikely to be the cause of iron deficiency. (See 'Decreased iron absorption' above and 'Medications' above and 'Foods that affect iron absorption' above.)
•Inadequate dietary iron – This generally applies to individuals in resource-limited settings, who may also have other causes of deficiency (bleeding, helminthic infections). A vegetarian diet can provide sufficient iron but may be inadequate in some individuals. (See 'Causes of reduced dietary intake' above.)
●Considerations for selected individuals – Some individuals have unique considerations related to iron needs and causes of iron deficiency, including individuals treated with erythropoietin or other erythropoiesis-stimulating agents (ESAs), those who participate in high-intensity athletics, those with hereditary disorders affecting iron handling, and people who are pregnant. (See 'Special scenarios' above.)
●Evaluation – Identifying and treating the cause of iron deficiency is an essential part of management, along with repleting iron stores. In resource-abundant settings, iron deficiency is likely to be due to blood loss (table 1).
We first evaluate and treat overt bleeding. In the absence of overt bleeding, we obtain bidirectional endoscopy in all males, non-menstruating females, and menstruating females >40 to 45 years of age. This is especially important in individuals with risk factors for colorectal cancer. (See 'Evaluation for the cause' above.)
●Follow-up – Chronic conditions generally require periodic monitoring. Iron stores generally require reassessment after a treatment course, with periodic re-checking and the interval extended if they remain normal. There should be a low threshold for retesting if symptoms of iron deficiency or the underlying condition recur. (See 'Treatment of the underlying condition and follow-up' above.)
●Treatment – Treatment is discussed separately. (See "Iron deficiency in infants and children <12 years: Treatment" and "Iron requirements and iron deficiency in adolescents" and "Treatment of iron deficiency anemia in adults" and "Anemia in pregnancy", section on 'Treatment of iron deficiency'.)
