Iron deficiency anemia (IDA) affects about one-third of the global population and has a significant impact on individuals with gastrointestinal (GI) disorders. Its multifactorial etiology includes chronic inflammation, impaired nutrient absorption, GI tract damage, inadequate dietary intake, increased iron requirements, and medication use. Effective clinical management of IDA involves accurate diagnosis, tailored treatment strategies, and ongoing monitoring. This review provides a comprehensive overview of the physiology and pathophysiology of IDA, with a focus on its prevalence in GI populations. The strategies for screening and diagnosis, the challenges posed by inflammation in interpreting iron studies, and individualized treatment considerations are discussed. Addressing these complexities is critical to improving clinical outcomes and the quality of life for those affected by IDA.

Introduction

Iron deficiency anemia (IDA) is among the most prevalent nutritional deficiencies globally, affecting approximately one-third of the population and representing a significant contributor to morbidity worldwide across age groups and socioeconomic classes.^1,2 IDA is commonly found in gastrointestinal (GI) disorders, including inflammatory bowel disease (IBD), celiac disease, and among post-bariatric surgery patients. The etiology of IDA involves disruptions of iron homeostasis that are driven by chronic inflammation, impaired nutrient absorption, and structural alterations to the GI tract.^1,3 The impact of iron deficiency (ID) even without the presence of anemia is not limited to physical symptoms but can also significantly impair quality of life, increase morbidity, and adversely affect pregnancy outcomes and chronic disease prognosis. If left untreated, IDA can exacerbate fatigue, cognitive deficits, and cardiovascular strain, emphasizing its importance in clinical practice.^1,2

Physiology and Pathophysiology

Iron is vital for critical physiological functions, including oxygen transport via hemoglobin, mitochondrial energy production, and enzymatic processes, making it essential for cellular and metabolic health.^1,2 Iron absorption occurs primarily in the duodenum after ferric iron (Fe³⁺) is reduced to ferrous iron (Fe²⁺) in the acidic gastric environment (refer to Figure 1). Heme iron from animal sources is absorbed more efficiently than non-heme iron from plant-based foods. The absorption mechanism differs between the two with non-heme iron being reduced to Fe²⁺ and transported into enterocytes by the divalent metal transporter 1 (DMT1), while heme iron enters via heme carrier protein 1 (HCP1). Vitamin C enhances the absorption of non-heme iron by reducing Fe³⁺ to Fe²⁺, thereby increasing its efficiency.² Within enterocytes, iron is either stored as ferritin or exported into the bloodstream by ferroportin, the only known cellular iron exporter.^2,3 

Once in circulation, iron binds to transferrin and is delivered to tissues, particularly the bone marrow, where it supports erythropoiesis. Excess iron is stored in hepatocytes and macrophages in the form of ferritin, ensuring enough iron is available to meet metabolic demands. Hepcidin regulates iron levels by inhibiting iron transporters, reducing the absorption of dietary iron and release of stored iron; therefore, elevated hepcidin can contribute to developing IDA.^1-3 Inflammation or chronic disease can elevate hepcidin levels, disrupting iron transport and utilization, often leading to IDA. 

Risk Factors and At-Risk Populations with Gastrointestinal Disorders

The development of IDA in GI disorders can stem from a range of systemic and localized factors. IBD, celiac disease, Helicobacter pylori (H. pylori) infection, gastric and foregut surgeries, and gastrointestinal cancer are among the primary GI disorders associated with IDA.^3-5 Key mechanisms include damage and inflammation of the GI tract, inadequate dietary intake, increased iron needs, and use of certain medications (Table 1).^3-14 

Inflammatory bowel disease

Studies have shown that approximately two-thirds of patients with IBD have anemia at the time of diagnosis.⁷ The pathogenesis of anemia in IBD is multifaceted and primarily driven by chronic intestinal blood loss due to mucosal ulcerations, impaired iron absorption from inflammation, and systemic cytokine effects that disrupt iron transport and utilization.⁵ This, combined with reduced dietary intake and intestinal damage, frequently leads to functional iron deficiency (FID) that can progress to IDA.

Celiac disease 

Studies have found that 12-82% of patients with new-onset celiac disease also have anemia.⁶ In celiac disease IDA is due to malabsorption caused by villous atrophy and inflammation in the small intestine triggered by gluten exposure.⁶ This damage impairs iron absorption which is further exacerbated by elevated hepcidin levels that restrict iron absorption and promote iron sequestration in storage cells. Even after adopting a gluten-free diet (GFD), ID may persist as the underlying malabsorption and inflammation may continue. According to Anniblae et al., only 50% of patients achieve normal iron levels after 12 months on a GFD, despite 94.4% recovering from anemia within the study period.⁸ Therefore, additional iron supplementation and consistent monitoring and management are necessary to restore and maintain adequate serum iron levels. 

Box 1. Signs and Symptoms Associated with Iron Deficiency1,20

• Pallor of the skin, conjunctiva, oral mucosa,
• nail bed (if with anemia)
• Koilonychias
• Fatigue
• Weakness
• Reduced work capacity
• Glossitis
• Angular cheilitis
• Alopecia
• Poor regulation of body temperature
• Decline in cognitive performance
• Pica
• Sleep disturbances

H. pylori infection

The bacterium H. pylori causes gastritis by destroying parietal cell mass and reducing gastric acid production leading to a less acidic environment in the gastric lumen. Since gastric acid is essential for reducing dietary iron, this increase in pH can hinder iron absorption.^5,9 Furthermore, H. pylori directly competes for iron by using iron-binding proteins on its outer membrane to support metabolic needs.¹⁰ Studies have shown that eradicating H. pylori improves hemoglobin and ferritin levels.^5,9 

Gastrointestinal Surgeries

Individuals who have undergone GI surgery, such as sleeve gastrectomy or Roux-en-Y gastric bypass (RYGB), are at an increased risk of IDA due to the restrictive and malabsorptive features of these procedures.^5,11 These procedures bypass key absorption sites, including the duodenum and proximal jejunum, reduce gastric acid production, and often involve a restrictive diet. A meta-analysis found that up to 26.5% of patients develop low ferritin levels within three years post-surgery.¹² Furthermore, a cross-sectional study revealed that over 50% of patients undergoing gastric bypass experience severe ID 10 years post-surgery, despite regular iron supplementation.¹¹ 

Gastrointestinal Cancer

Cancer is a major pathologic diagnosis that increases the risk of IDA with studies showing 8–15% of patients diagnosed with GI malignancy have a concomitant diagnosis of IDA.¹³ Etiologic mechanisms in colorectal, gastric, and esophageal cancers include frequent bleeding, mucosal damage, and an inflammatory response that elevates hepcidin levels.¹³ The prevalence of IDA increases during treatment with up to 60% of patients with GI cancers experiencing IDA during their disease course. IDA is often compounded by cancer treatments, reduced dietary intake, and poor appetite which can aggravate fatigue and quality of life, ultimately complicating treatment outcomes and prognosis.³

Screening and Diagnosis

Iron screening guidelines have been developed for several at-risk GI patient populations (Table 2).^7,15–19 Iron studies should also be considered based on symptomatology and physical exam findings (Box 1).^1,20 ID can be identified using a combination of serum laboratory markers including hemoglobin, ferritin, iron, total iron binding capacity (TIBC), and transferrin saturation (Tsat). Because anemia does not develop until ID is more advanced, a normal serum hemoglobin value should not preclude the diagnosis of ID.²¹ Similarly, the development of anemia may be multifactorial due to causes other than or in conjunction with ID, warranting additional workup. Circulating ferritin reflects iron tissue stores and is generally the first iron biomarker to decline in response to inadequate iron intake.²¹ Decreases in serum iron and an adaptive rise in TIBC follow, whereas further iron depletion compromises erythropoiesis. 

As discussed previously, the presence of active inflammation complicates the evaluation of iron studies. Given that some patients with GI conditions may exhibit chronic, low-grade inflammation or acute inflammation during disease flares, C-reactive protein (CRP) should be obtained in conjunction with iron studies. Because ferritin is a positive acute phase reactant, its elevation can mask an ID.¹⁴ There is a lack of consensus on how to diagnose ID in the setting of inflammation, yet ferritin values of up to 100 ng/mL are widely suggested as an indicator of ID when CRP is elevated.^7,14,22,23 Although stored iron may be sufficient, pro-inflammatory cytokines upregulate the synthesis of hepcidin, which reduces iron absorption and mobilization by suppressing the expression of ferroportin.^7,14,22 This leads to FID where the availability of serum iron to participate in erythropoiesis is insufficient. Inflammatory mediators may also interfere with erythropoiesis and shorten the lifespan of red blood cells.²⁴ FID along with these other inflammation-driven effects contribute to what is considered anemia of chronic disease (also called anemia of inflammation). Thus, patients may present with an absolute ID, FID, or a combination.^7,23,25 The ratio of serum iron to TIBC, which is used to calculate Tsat, indicates the amount of iron bound to transferrin and available for tissue distribution. Low Tsat is observed in both absolute ID and FID.^7,23,25 An overview of iron biomarkers is presented in Table 3.

Table 1. Mechanisms of Iron Deficiency Anemia in Gastrointestinal Disorders^3–14

Table 2. Recommendations for Iron Screening in Gastrointestinal Disorders^7,15-19

Treatment of Iron Deficiency

Regardless of the presence of any signs or symptoms of ID, all patients should receive treatment when biochemical ID, FID, or IDA is present. Treatment for ID, FID, or IDA involves an understanding of dietary supplement regulation, third-party certification, and the bioavailability of various product formulations. With these factors understood, the clinician can then devise an appropriate treatment and monitoring plan. Additionally, the treatment strategy will differ based on the severity of the ID and the presence of anemia. The treatment of life-threatening anemia where red blood cell (RBC) transfusion is often necessary with or without additional iron infusions is outside of the scope of this article. However, the clinician should note that each unit of RBC typically contains 200 mg of iron which can impact the treatment strategy.^26,27 The treatment reviewed focuses on those being treated in the outpatient setting for the nonpregnant adult.

Table 4. Treatment Options for Iron Deficiency^7,27,29,30

Bioavailability is reported as the amount of the supplement or drug that enters circulation and can be utilized by the body.²⁸ Iron formulations have varying bioavailability with oral formulations having the poorest bioavailability and intravenous formulations having 100% bioavailability (refer to Table 4).^7,27,29,30 Since the body can increase the amount of intestinal iron absorbed based on iron status, the presence of ID, FID or IDA will increase dietary/oral iron absorption. In severe cases of anemia or when oral iron supplementation is contraindicated, intravenous iron should be selected.

Oral Formulations

Oral iron absorption can be hindered by the simultaneous consumption of food (e.g., tannins, calcium, phytates) and certain medications such as proton pump inhibitors.²⁷ Therefore, efficacy is improved when taken away from meals. The most commonly administered oral iron formulations include ferrous sulfate, ferrous gluconate, polysaccharide-iron complex, and ferrous fumarate. Absorption and the dose of elemental iron present differ amongst these formulations which may contribute to varying degrees of GI symptoms. Polysaccharide-iron complex is a third-generation ferric iron formulation designed to improve palatability with fewer GI symptoms. However, in the absence of randomized clinical control trials comparing dose-equivalent iron formulations and the impact on GI symptoms and/or palatability, no conclusions can be made. Additionally, ferrous formulations such as ferrous sulfate, ferrous gluconate, and ferrous fumarate are readily absorbed in the GI tract whereas ferric formulations must be reduced by ferrireductase before absorption. Despite these differences, each formulation can be effective in treating and preventing ID, FID, and IDA. The American Gastroenterological Association (AGA) endorses the use of ferrous sulfate given its cost-effectiveness and lack of data suggesting any oral iron supplement is advantageous over another and that supplementation should be consumed with vitamin C to improve absorption.²⁹ However, recommendations for the concomitant use of vitamin C with ferrous iron formulations are theoretical, and more research is needed to support this practice.

Historically, daily to three times daily dosing was the most common method for iron supplementation. However, the frequency of dosing is currently debated as less frequent dosing is hypothesized to improve iron supplementation compliance and intestinal absorption. With GI side effects (i.e., nausea, constipation, and epigastric pain) being common, the risk of noncompliance with iron supplementations is of concern. A reduction in GI side effects with alternate day dosing has been reported by some,^31,32 while other studies have shown a lack of improvements.^33-36 With data suggesting iron supplementation impacts circulating hepcidin levels, and the concern of noncompliance, investigations into alternate daily dosing were evaluated.³⁶ Stoffel and colleagues investigated the impact of daily and alternate-day iron dosing on hepcidin levels and iron absorption which were both superior in the alternate-day group.^33,34 This study, along with others, increased awareness of the potential benefits of alternate daily dosing to improve anemia. However, when this strategy was applied to severely anemic individuals (N=200) in a randomized control trial, there was no difference in serum hemoglobin levels between those on daily (60 mg total) or alternate day dosing (120 mg) (p=0.47). While a definitive dosing strategy is unavailable, it is reasonable to consider alternate-day dosing to provide GI relief when present and when compliance with daily dosing is of concern.³⁶ The AGA expert consensus statement endorses dosing oral iron no more than once daily since there is a lack of evidence for improved absorption with increased frequency and that the risk of side effects increases.²⁹

Intravenous Formulations

Intravenous iron formulations are 100% bioavailable. Intravenous formulations are typically administered under medical supervision and are more commonly prescribed for those unable to consume oral iron, those unresponsive to oral iron, or those with severe anemia. In clinical practice, iron deficit equations are typically used to determine the appropriate dose such as: ²⁷

Hemoglobin iron deficit (mg) = weight (kg) x (14 – Hgb) x 0.24 + 500)

Iron is not routinely included in PN admixtures as intravenous iron has the highest risk of iron toxicity, anaphylaxis (although rare), and incompatibility, particularly with lipid-containing formulations.³⁷ IV iron preparations available in the US include iron dextran, iron sucrose, ferric gluconate, ferumoxytol, and ferric carboxymaltose.³⁷ Iron sucrose and ferric gluconate have a generally lower risk of hypersensitivity and the absence of a requirement for test dosing; however, only iron dextran is compatible with 2-in-1 PN at amino acid concentrations higher than 2%, while it remains incompatible with total nutrient admixtures.³⁷ Furthermore, concern of hypophosphatemia has been reported in those on recurrent intravenous infusions (most commonly with ferric carboxymaltose).²⁸ The AGA recommends intravenous iron for those with IBD, IDA, active inflammation in the GI tract, poor tolerance to oral supplementation, poor response to oral iron, and ongoing bleeding that is unresponsive to oral supplementation.²⁹

Iron Supplementation Recommendations

It is common that clinicians may omit pertinent details for the patient to carry out the finalized recommendation. The finalized prescription or recommendation for ID must include the following items: date of the prescription, patient name, patient date of birth, provider name and address, name of the iron formulation, dosage strength, dosage form, delivery route, dose frequency, pertinent directions for administration, quantity to be provided by the pharmacist or purchased by the patient, number of refills, and the prescriber signature. Since the Dietary Supplement Health and Education Act of 1994 allows dietary supplements to be marketed without prior FDA approval, third-party certification of dietary supplements is recommended (e.g., ConsumerLab.com, National Sanitation Foundation-NSF, United States Pharmacopia-USP).²⁹ Third-party verification can provide insight into the bioavailability of some iron supplements and can be useful to patients looking for over-the-counter iron formulations.

Monitoring and Evaluation

Monitoring treatment strategies are essential to ensure ID, FID, and IDA have been corrected and to prevent toxicities from occurring. As outlined in the assessment section, biochemical indices, signs and symptoms of ID, FID or IDA should be monitored until correction. Refer to Table 4 for suggestions for monitoring parameters. 

Case Study

A 50-year-old male with ulcerative colitis (diagnosed 10 years prior) presents in the clinic with fatigue and 3-4 liquid stools daily (50% with overt blood). At home, a patient takes azathioprine 100 mg daily, a standard multivitamin, and ferrous sulfate 65 mg daily (no longer taking x 2 months due to GI effects). Most recent laboratory findings are found below:

• Hemoglobin 9.5 g/dL (14.0-17.5 g/dL)
• Ferritin 16 ng/mL ( 12-300 ng/mL)
• CRP 25 mg/dL (<1.0 mg/dL)
• Serum iron 30 mcg/dL (60-160 mcg/dL)
• TIBC 370 mcg/dL (300-360 mcg/dL)
• Tsat 8.1% (20-50%)

The clinician recommends a referral to hematology for the management of recurrent IDA. Due to a history of poor oral iron tolerance and active inflammation limiting GI iron absorption, an intravenous iron infusion is recommended. Additionally, the clinician changes the standard multivitamin without iron to a daily multivitamin with iron (containing 18 mg of elemental iron). Laboratory parameters are recommended to be repeated in 3 months and include a CBC, iron studies (ferritin, Tsat, TIBC, serum iron), and CRP. 

References

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