Iron deficiency anemia (IDA) is the most recognized type of anemia in patients with celiac disease (CD) and may be present in over half of patients at the time of diagnosis. Folate and vitamin B12 malabsorption, nutritional deficiencies, inflammation, blood loss, development of refractory CD, and concomitant Heliobacter pylori infection are other causes of anemia in such patients. The decision to replenish iron stores and the route of administration (oral or intravenous) are controversial due, in part, to questions surrounding the optimal formulation and route of administration.
Iron is an essential nutrient to life, and its role in biology is enormous . In fact, iron is required for erythropoiesis, oxidative, metabolism, and enzymatic activities, and it is a cofactor for mitochondrial respiratory chain enzymes, the citric acid cycle, and DNA synthesis . It also promotes the growth of immune system cells. Iron deficiency (ID) is the most common deficiency state in the world, affecting more than two billion people globally. Although it is particularly prevalent in less-developed countries, it remains a significant problem in the developed world, where other forms of malnutrition have been almost eliminated . Celiac disease (CD) is a well-recognized cause of IDA, even in asymptomatic patients, and, therefore, it must be considered in the differential diagnosis of IDA . The prevalence of CD among people with anemia (and vice versa), its clinical consequences, and its management in specific contexts is discussed here, providing healthcare professionals with practical guidance and algorithms.
Iron is an essential micronutrient with well-established contributions to body functions, such as the formation of red blood cells and hemoglobin, oxygen transport, cell division, energy metabolism, immunity, and cognition .
The body and cells need a very precise amount of iron: too much can be toxic and too little is bad for the metabolism . Due to this toxicity, and in the absence of active excretion mechanisms, intestinal iron absorption is extremely limited and regulated tightly (barely 1–2 mg/day) to compensate for natural losses, and it is fundamentally based on recycling and a very precise circular economy. Therefore, internal turnover of iron is essential to satisfy the requirements of erythropoiesis (20–30 mg/d) .
In the cell, iron can be stored in two forms: in the cytosol as ferritin, and, after breakdown of ferritin, in the lysosomes as hemosiderin. Iron export from macrophages to transferrin is accomplished primarily by ferroportin 1, the same iron-export protein as expressed in the duodenal enterocyte . The liver is the other main storage organ for iron, but RBC mass is the main storage “place”.
The positive regulation of hepcidin by the inflammatory response pathways to stress, its hepatic synthesis through (IL 6) interleukin 6, is an important critical event that triggers withdrawal and systemic iron sequestration due to its negative regulation of iron. Ferroportin causes an increase in iron levels, which, in turn, limit iron transport from the liver and macrophages to plasma; furthermore, it also inhibits the absorption of iron from the diet in the duodenum, which leads to iron restriction. Iron absorption in the presence of increased hepcidin is inhibited.
Of great interest is the study conducted by Shahriari et al., in which 184 children, including 92 IDA patients who responded to treatment using iron supplements, 45 non-responding iron deficient patients, and 47 healthy individuals, with the maximum age of 18 years, participated in serologic screening (with anti-TTG antibody and anti-endomysial antibody) for CD. Patients with at least one positive serology test underwent multiple mucosal biopsy from the bulb and duodenum. Interestingly, the frequency of positive serologic tests in the group with IDA resistant to treatment was prominently higher than that in the other two groups ( p < 0.001). Among the patients with a positive serologic celiac test who underwent endoscopy and biopsy, no histologic evidence of CD was observed . They were diagnosed as potentially having CD, patients with normal small intestinal mucosa who are at increased risk of developing CD as indicated by positive CD serology . This suggests that even among patients with positive celiac serology and the absence of histological lesions (“potential celiac”), ID or IDA may still be present. This observation is shared by our own clinical practice.
Remarkably, despite the information provided in the literature, the index of suspicion for the diagnosis of CD among patients with ID or IDA is surprisingly low. Spencer et al. electronically distributed a survey to primary care physicians (PCPs) who are members of the American College of Physicians. Respondents were asked whether they would test for CD (serologic testing, referral for esophagogastroduodenoscopy (EGD], or referral to GI) in hypothetical patients with new IDA. Testing for CD varied significantly according to patient characteristics but, globally, PCPs are under-testing for CD in patients with IDA, regardless of age, gender, race, or post-menopausal status. In addition, most PCPs surveyed reported that they do not strictly adhere to established guidelines regarding a confirmatory duodenal biopsy in a patient with positive serology for CD .
Patients with IDA of unknown etiology are frequently referred to a gastroenterologist because, in most cases, the condition has a gastrointestinal origin. On the other hand, it is well known that only a minority of CD patients present with classical malabsorption symptoms of diarrhea and weight loss, whereas most patients have subclinical or silent forms in which IDA can be the sole presentation . Zamani et al. investigated the prevalence of CD in a large group of patients with IDA of obscure origin. . Of the 4120 IDA patients referred to a hematology department, 206 (95 male) patients were found to have IDA of obscure origin after an extensive evaluation of the gastrointestinal tract. Out of a total of 206 patients (14.6%), 30 had gluten-sensitive enteropathy (GSE) based on a positive serological test and abnormal duodenal histology. A gluten-free diet (GFD) was advised for all the GSE patients. Some results of this research deserve to be highlighted: The average duration of anemia was 3.6 +/− 1.4 years. Most of the GSE patients (73.3%) did not report any gastrointestinal symptoms. Consequently, physicians may fail to consider GSE as a cause of IDA when gastrointestinal symptoms are absent or nonspecific. These patients had been treated with oral iron for a mean duration of 1.9 years. Anemia improved in only eight patients (26.8%) treated with oral iron supplementation before GSE diagnosis. In GSE patients, the hemoglobin level was inversely correlated with the severity of the histological injury. Patients with Marsh 3 lesions had the most severe anemia, consistent with the role of impaired intestinal absorption in the pathogenesis of IDA. Many authors consider the presence of villous atrophy (e.g., Marsh 3) as one of the major criteria for diagnosing CD . To avoid this controversy in the definition of CD, the authors used the term “gluten sensitive enteropathy” rather than CD to describe patients with any degree of intestinal damage together with positive serologic tests. In this study, the authors showed a significant objective improvement in hemoglobin levels with GFD alone in patients with positive serology but no villous atrophy (e.g., Marsh 1 or 2). This would be an important point concerning the route of iron administration (oral versus intravenous) in patients with or without villous atrophy (see below). Furthermore, GFD could improve anemia in IDA patients who have positive tTGA/EMA and mild duodenal lesions without villous atrophy.
Iron is an important micronutrient, and CD constitutes one of the groups at the highest risk of ID. ID during the first year of life occurs at a time of rapid neural development and when morphological, biochemical, and bioenergetic alterations may all influence future functioning . The brain is the most vulnerable organ during critical periods of development . Iron is present in the brain from very early in life, when it participates in the neural myelination processes , learning, and interacting behaviors, and iron is needed by enzymes involved in the synthesis of serotonin and dopamine neurotransmitters . In adults, IDA results in fatigue and diminished muscular oxygenation, which may affect muscle strength and quality and, subsequently, physical performance. In both populations (children and adults), iron deficiency leads to increased vulnerability to infections, especially of the respiratory tract. Consequently, it is important to replenish iron stores quickly, safely, and effectively in any patient with a gastrointestinal source of ID, either through blood loss or malabsorption.
The decision to replenish iron stores by oral or intravenous iron administration is controversial  and depends primarily on the severity of symptoms, the tolerance and efficiency of oral iron, and those factors that predict a poor response to oral iron (e.g., severity of histological lesion; poor adherence to GFD; or blood loss due to mucosal lesions, such as concomitant IBD, jejunoileitis, or malignancy). Figure 2 is an algorithm proposed by the authors for decision making. This proposal should be validated by well-designed studies comparing the efficiency and safety of both replenishment routes in the different settings indicated and their cost-effectiveness.
GFD alone may improve mild forms of IDA in patients with CD . In fact, GFD is the primary means of preventing anemia in CD patients after diagnosis. However, recovery may be slow , and the administration of iron may accelerate the replenishment of iron stores in the body and thus the resolution of ID-dependent symptoms. This strategy can be useful especially in those patients with mild forms of enteropathy (Marsh 1-3a), especially if adherence to the GFD is not good. There are many barriers to following a GFD because gluten is present in many foods, and the cross-contamination is always a cause for concern. Dietary counseling that provides adequate and thorough information to the patients and their families regarding this disease and the need for lifelong adherence to a GFD is necessary. During follow-up, it is important to investigate for a micronutrient deficiency, such as of iron (a complete blood count plus serum ferritin), calcium, folic acid, vitamin B-6, and vitamin B-12 . In contrast, replacement therapy with oral iron formulations is often ineffective and poorly tolerated in patients with more advanced forms of enteropathy (Marsh 3b-3c), because unabsorbed iron impregnates and irritates the duodenal mucosa and is the cause of numerous adverse effects . Table 1 shows some considerations of interest in relation to oral iron replacement . By way of summary: Ferrous sulphate (FS) is the most undertaken therapy for oral iron replacement . In children, the recommended iron dose is 2–6 mg/kg/day in terms of elemental iron. In adolescents and adults, it is 100–200 mg daily. Sometimes, these high doses of oral iron cause a paradoxical decrease in iron absorption due to factors such as elevated plasma hepcidin levels . In our practice, formulations that provide 40–80 mg of elemental iron, when administered once (80 mg) or twice (40 mg/12 h) daily, are equally effective and better tolerated. Toxicity associated with oral iron is higher in elderly patients, and such patients should be treated with lower doses. In fact, doses of 15, 50, or 150 mg of elemental iron may be equally effective in raising hemoglobin and ferritin levels, while adverse effects are significantly less common with lower doses . Strategies for reducing side effects and improving tolerability include: o Limiting the dose (≤80–100 mg of elemental iron per day). o Dividing the total dose and taking it in two daily doses or increasing the time between doses (e.g., every two days) . o Taking iron after dinner (reduces absorption but improves tolerance). o Changing the formulation (e.g., from ferrous sulphate to ferrous gluconate) or presentation used (e.g., from tablets to oral solution, which makes it easier to titrate doses). o Some proposed solutions to improve oral iron absorption in CD include the use of probiotics ( Lactobacillus plantarum 299v and Bifidobacterium lactis HN019 )  or prebiotics (oligofructose enriched inulin) , as well as the use of ferrous bisglycinate chelate (FBC), or the most recent Feralgine ® , a compound of FBC and alginic acid that has recently been developed to improve the bioavailability and tolerability profile. Feralgine ® and FBC are effective at a dosage of 30–40% compared to FS. Several studies have demonstrated the efficacy and safety of FBC in the treatment of IDA in both adults and children, without showing side effects . In addition, recent studies conducted in adult celiac patients confirmed the good level of absorption and tolerance of Feralgine ® in patients with anemia as well as in non-celiac subjects and in those with onset CD . o Another alternative aimed at reducing the risk of adverse effects associated with iron sulphate is sucrosomial iron (SI). SI a preparation of ferric pyrophosphate covered by a phospholipids and sucrester membrane, can be absorbed across intestinal epithelium by an alternative route, non-mediated by the DMT-1 carrier , which may contribute to the reduction of side effects and the prevention of iron instability in the gastrointestinal tract. A study evaluated the efficacy and safety of a new SI formulation (30 mg of iron/day) versus iron sulfate (105 mg of iron/day), in patients with CD. After a follow-up of 90 days both groups showed an increase in Hb levels compared to baseline (+10.1% and +16.2% for sucrosomial and sulfate groups, respectively), and a significant improvement in all iron parameters, with no statistical difference between the two groups. However, patients treated with SI reported a lower severity of abdominal symptoms, such as abdominal and epigastric pain, abdominal bloating, and constipation, and a higher increase in general well-being (+33% vs. +21%) compared to the iron sulfate group . Therefore, SI can be effective in providing iron supplementation in difficult-to-treat populations, such as patients with CD, IDA, and known intolerance to iron sulfate. Response to oral iron therapy can be considered satisfactory when an increase in hemoglobin levels of at least 2 g/dL is observed within 3–4 weeks, which is also associated with an improvement in physical well-being and anemia-dependent signs and symptoms, including depapillation of the sides of the tongue, which is a good indicator of recovery. For patients with persistent anemia or ID and doubts about correct adherence to the GFD, it may be important to investigate the presence of gluten immunogenic peptides (GIPs) in fecal or urine samples, as these are present in a significant proportion of patients who declare a correct adherence to the diet. This policy may avoid unnecessary biopsies or limit them to cases where symptoms persist despite good nutritional advice and repeatedly negative GIP results . If oral iron is not tolerated, or not absorbed due to intestinal inflammation, then intravenous iron should be given.
|Guidance and Considerations in Relation to Oral Iron Replacement|
|The dose of oral iron depends on patient age, the estimated iron deficit, how quickly it needs to be corrected, and side effects.|
|Absorption improves when iron is taken in a moderately acidic medium; therefore, it is recommended that iron be taken with ascorbic acid (250–300 mg) or half a glass of orange juice. Some ferric gluconate formulations contain ascorbic acid with 80 mg of elemental iron.|
|Some food components, such as phosphates, phytates, and tannates (which are found in coffee, tea, cocoa, and red wine), inhibit iron absorption. Other foodstuffs that impair iron absorption are cereals, dietary fiber, eggs, milk, and generally any foods with a high calcium content. Many of these items regularly form part of patients’ breakfasts. The summary of product characteristics for most oral iron products therefore recommend taking oral iron at least 1 h before or 2 h after eating. However, although the administration of oral iron together with food decreases absorption, it improves tolerance and is one of the strategies used by many doctors in the event of side effects (see above).|
|Iron is best absorbed as the ferrous (Fe++) salt in a mildly acidic medium. Gastric acidity is helpful and medications that reduce gastric acid (e.g., antacids, histamine receptor blockers, proton pump inhibitors) may impair iron absorption. Other medications that impair oral iron absorption are calcium supplements and certain antibiotics (quinolones and tetracyclines), and, therefore, oral iron should be taken at least 2 h before or after these medications.|
|Enteric-coated or sustained-release capsules are less efficient for oral absorption because iron is released too far distally in the intestinal tract (or not at all).|
|Gastrointestinal symptoms associated with taking oral iron are common and include metallic taste, dyspepsia, nausea, vomiting, flatulence, diarrhea, and constipation. Some patients may also be bothered by the dark green or tarry stools (they should be warned if they are to undergo a colonoscopy). As a result of this, compliance with oral iron administration may be low. The severity and impact of these effects has been demonstrated in various systematic reviews and meta-analyses of randomized studies , and they are estimated to affect 30–43% of patients, depending on the formulation used. Supplements containing smaller amounts of elemental iron are associated with less gastrointestinal toxicity, especially in elderly patients . Taking iron after dinner reduces absorption but improves tolerance. The reader is referred to the recommended doses in Section 8.6 of the text.|
CD (and, for that matter, any other disease causing villous atrophy) is a classic scenario where the results of oral iron replacement are poor due impaired absorption inherent to mucosal injury. These children could benefit from a strategy focused on intravenous iron administration under certain conditions (see below). In a retrospective cohort study, a total of 116 IV iron carboxymaltose infusions were administered to 72 patients with IDA refractory to oral iron and were shown to be safe and highly effective in a small yet diverse population of infants, children, and adolescents .