Parenteral iron therapy in children with iron deficiency anemia

Iron deficiency anemia(IDA)continues to be a global public health problem.Oral iron is the universally accepted first-line therapy,and most children have a prompt and favorable response to oral formulations.In subsets of children who fail to respond due to intolerance,poor adherence,or inadequate intestinal absorption,parenteral iron is indicated.Despite numerous studies in adults with IDA of diverse etiologies,pediatric studies on parenteral iron use are very limited.Although mostly retrospective and small,these studies have documented the efficacy and safety profile of intravenous iron formulations.In this editorial the author comments on the most important published data and underscores the need to seriously consider parenteral iron use in children unresponsive to oral therapy.

Inpatient management of iron deficiency anemia in pediatric patients with inflammatory bowel disease: A single center experience

BACKGROUND Screening for iron deficiency anemia(IDA)is important in managing pediatric patients with inflammatory bowel disease(IBD).Concerns related to adverse reactions may contribute to a reluctance to prescribe intravenous(IV)iron to treat IDA in this population.AIM To track the efficacy and safety of IV iron therapy in treating IDA in pediatric IBD patients admitted to our center.METHODS A longitudinal observational cohort study was performed on 236 consecutive pediatric patients admitted to our tertiary IBD care center between September 2017 and December 2019.92 patients met study criteria for IDA,of which 57 received IV iron,17 received oral iron,and 18 were discharged prior to receiving iron therapy.RESULTS Patients treated with IV iron during their hospitalization experienced a significant increase of 1.9(±0.2)g/dL in mean(±SE)hemoglobin(Hb)concentration by the first ambulatory follow-up,compared to patients who received oral iron 0.8(±0.3)g/dL or no iron 0.8(±0.3)g/dL(P=0.03).One out of 57(1.8%)patients that received IV iron therapy experienced an adverse reaction.CONCLUSION Our findings demonstrate that treatment with IV iron therapy is safe and efficacious in improving Hb and iron levels in pediatric patients with IDA and active IBD.

Iron-Deficiency Anemia Management in Gynecological Surgery: A Review of Current Evidence and Best Practices

Purpose: Due to the high prevalence of iron deficiency anemia in women undergoing gynecological surgeries and its association with worse postoperative results, it is necessary to identify and treat anemia preoperatively. However, although anemia and iron deficiency are significant global health problems, there are still disparities in the recognition and implementation of “Patient Blood Management” (PBM) as a comprehensive approach to mitigating the risks associated with these diseases. The purpose of the study is to review best practices for the treatment of anemia based on the Enhanced Recovery After Surgery (ERAS) protocol and PBM recommendations. Methods: This study reviewed the literature on preoperative iron deficiency anemia in patients undergoing gynecological surgery. We identified references through searches in PubMed using relevant search terms. Results: Among the various strategies used in PBM, perhaps the most important is the early detection and management of anemia. In gynecological surgery, there are several approaches to reducing perioperative blood loss, highlighting the use of gonadotropin-releasing hormone (GnRH) agonists (aGnRh) and antifibrinolytics. Oral and intravenous iron supplementation can be performed in addition to blood transfusion to treat anemia. Conclusion: Addressing preoperative and postoperative anemia through systematic correction, following the guidelines of the ERAS protocol and PBM guidelines, is essential to improving perioperative outcomes in women undergoing gynecological surgery.

Efficacy and Safety of Iron Isomaltoside Compared with an Oral Iron Supplement in the Management of Patients with Iron Deficiency Anemia

Objective: To evaluate the treatment outcome of iron isomaltoside compared with an oral iron supplement in the management of iron deficiency anemia (IDA). Methods: The study included patients with IDA who visited the Outpatient Clinic of the Department of Hematology, the Affiliated Hospital of Qingdao University from October 2021 to August 2022 and met the inclusion and exclusion criteria. According to the actual application of iron supplementation, the patients were divided into two groups: iron isomaltoside treatment group and oral iron treatment group. Baseline measurements were collected before the start of treatment, and measurements were collected subsequently at intervals of 1 week, 1 month, and 3 months. The hematological parameters analyzed included Hemoglobin (Hb), Mean corpuscular hemoglobin (MCH), Mean Hemoglobin content (MCH), Mean corpuscular Hemoglobin concentration (MCHC), and Platelet (Plt). Safety data and adverse event profiles were recorded. Results: Intra-group comparisons: After 1 month of treatment, the Hb significantly improved (P 0.05). Inter-group comparisons: The biochemical parameters were significantly improved (P 0.05) in the iron isomaltoside group compared with those in the oral iron group after 1 month of iron supplementation in patients with mild and moderate anemia. Adverse reactions were tolerable for the patients in both iron isomaltoside group and oral iron group. Only 1 patient in iron isomaltoside group developed anaphylactic shock during medication and recovered after aggressive rescue. Conclusions: Iron isomaltoside which increases Hb more rapidly compared with the oral iron supplementation has few adverse reactions and good acceptance.

Role of iron deficiency anemia in inflammatory bowel disease

Inflammatory bowel disease(IBD)is a relapsing chronic inflammatory disorder of the small and large gut with rising incidence and prevalence worldwide.Iron deficiency anemia is one of the most common extraintestinal manifestations of IBD,which correlates with the disease activity and tendency to relapse even after successful management.Anemia affects various aspects of quality of life,such as physical,cognitive,emotional,and workability,as well as healthcare costs.The anemia in IBD can be due to iron deficiency(ID)or chronic disease.The relative frequency of ID in IBD is 60%,according to some studies,and only 14%receive treatment.The evaluation of ID is also tricky as ferritin,being an inflammatory marker,also rises in chronic inflammatory diseases like IBD.The review of anemia in IBD patients involves other investigations like transferrin saturation and exploration of other nutritional deficiencies to curb the marker asthenia with which these patients often present.It underscores the importance of timely investigation and treatment to prevent long-term sequelae.We can start oral iron therapy in certain circumstances.Still,as inflammation of the gut hampers iron absorption,an alternative route to bypass the inflamed gut is usually recommended to avoid the requirement for blood transfusions.

Flammulina velutipes polysaccharide-iron (Ⅲ) complex used to treat iron deficiency anemia after being absorbed via GLUT2 and SGLT1 transporters

Iron deficiency anemia(IDA)is a common nutritional problem, but traditional iron supplements cause many adverse reactions. Thus, the development of a novel iron supplement might be significant for the treatment of IDA. This study aimed to study the transport mechanism of Flammulina velutipes polysaccharide-iron complex(FVP1-Fe(Ⅲ))in Caco-2 cells and the therapeutic effect on IDA rats, as well as the influence on gut microbiota in vivo. These results showed that in vitro, the uptake of FVP1-Fe(Ⅲ)was mediated by sodium-dependent glucose transporter-1(SGLT1)and facilitated glucose transporter-2(GLUT2)and GLUT2 played a dominant function. The multidrug resistance-associated protein-2(MRP-2)was involved in the efflux of FVP1-Fe(Ⅲ)across the Caco-2 cells. In vivo, FVP1-Fe(Ⅲ)had a better restorative effect on blood parameters and iron status indicators in rats with IDA as compared with FeSO_4 and exerted this effect by downregulating the expression of hepcidin. FVP1-Fe(Ⅲ)could also regulate gut microbiota dysbiosis in iron deficiency rats by returning the relative abundance of gut microbiota to the normal level. Besides, as a dietary factor, vitamin C(vit C)could enhance the therapeutic effect of FVP1-Fe(Ⅲ). These present findings showed that FVP1-Fe(Ⅲ)could be exploited as a novel iron supplement to treat IDA.

Carbon Monoxide Modulates Auxin Transport and Nitric Oxide Signaling in Plants under Iron Deficiency Stress

Carbon monoxide(CO)and nitric oxide(NO)are signal molecules that enhance plant adaptation to environmental stimuli.Auxin is an essential phytohormone for plant growth and development.CO and NO play crucial roles in modulating the plant’s response to iron deficiency.Iron deficiency leads to an increase in the activity of heme oxygenase(HO)and the subsequent generation of CO.Additionally,it alters the polar subcellular distribution of Pin-Formed 1(PIN1)proteins,resulting in enhanced auxin transport.This alteration,in turn,leads to an increase in NO accumulation.Furthermore,iron deficiency enhances the activity of ferric chelate reductase(FCR),as well as the expression of the Fer-like iron deficiency-induced transcription factor 1(FIT)and the ferric reduction oxidase 2(FRO2)genes in plant roots.Overexpression of the long hypocotyl 1(HY1)gene,which encodes heme oxygenase,or the CO donor treatment resulted in enhanced basipetal auxin transport,higher FCR activity,and the expression of FIT and FRO2 genes under Fe deficiency.Here,a potential mechanism is proposed:CO and NO interact with auxin to address iron deficiency stress.CO alters auxin transport,enhancing its accumulation in roots and up-regulating key iron-related genes like FRO2 and IRT1.Elevated auxin levels affect NO signaling,leading to greater sensitivity in root development.This interplay promotes FCR activity,which is crucial for iron absorption.Together,these molecules enhance iron uptake and root growth,revealing a novel aspect of plant physiology in adapting to environmental stress.

Ratio of hemoglobin to mean corpuscular volume: A new index for discriminating between iron deficiency anemia and thalassemia trait

BACKGROUND Iron deficiency anemia(IDA)and thalassemia trait(TT)are the most common microcytic and hypochromic anemias.Differentiation between mild TT and early IDA is still a clinical challenge.AIM To develop and validate a new index for discriminating between IDA and TT.METHODS Blood count data from 126 patients,consisting of 43 TT patients and 83 IDA pa-tients,was retrospectively analyzed to develop a new index formula.This formula was further validated in another 61 patients,consisting of 48 TT patients and 13 IDA patients.RESULTS The new index is the ratio of hemoglobin to mean corpuscular volume.Its sen-sitivity,specificity,accuracy,Youden’s Index,area under the receiver operating characteristic curve,and Kappa coefficient in discriminating between IDA and TT were 93.5%,78.4%,83.3%,0.72,0.97,and 0.65,respectively.CONCLUSION This new index has good diagnostic performance in discriminating between mild TT and early IDA.It requires only two results of complete blood count,which can be a very desirable feature in under-resourced scenarios.

Iron versus Iron and Vitamin B6 Supplementation in Treatment of Iron Deficiency Anemia during Second Trimester of Pregnancy: Quasi Experimental Trial

Background: Anemia is one of the most prevalent complications during pregnancy. It is commonly considered a risk factor for poor pregnancy outcomes and can result in complications that threaten the life of both mother and fetus, such as preterm birth, and low birth weight. There is clear evidence to support prompt treatment in all patients with iron deficiency anemia because it is known that treatment improves quality of life and physical condition as well as alleviates fatigue and cognitive deficits. Objective: The aim of the study was to evaluate the value of addition of vitamin B6 to iron in treatment of iron deficiency anemia in pregnant women during the second trimester. Patients and Methods: The study was done by giving anemia pregnant women iron therapy and vitamin B6 which represent group A and iron therapy alone which represents group B. For each pregnant woman, age, parity and gestational history were taken before treatment. All pregnant women took their allocated treatment regularly for three weeks after diagnosis of iron deficiency anemia with complete blood picture and followed up after three weeks. Results: Results of the study revealed that there was no statistically significant difference between the two groups of therapy according to the hemoglobin level before treatment (p-value = 0.734), statistically significant higher mean value in after treatment than before treatment (p-value = 0.048), there was a significant difference in the rate of change of hemoglobin (p-value = 0.011) and body mass index (p-value 0.001). Conclusion: Iron and vitamin B6 seems to increase hemoglobin level more than iron only. Thus, in pregnant women with iron deficiency anemia iron plus vitamin B6 may be considered as a more effective alternative treatment than iron only.

Role of small bowel capsule endoscopy in the diagnosis and management of iron deficiency anemia in elderly: A comprehensive review of the current literature

Iron deficiency anemia(IDA)is common and often under recognized problem in the elderly.It may be the result of multiple factors including a bleeding lesion in the gastrointestinal tract.Twenty percent of elderly patients with IDA have a negative upper and lower endoscopy and two-thirds of these have a lesion in the small bowel(SB).Capsule endoscopy(CE)provides direct visualization of entire SB mucosa,which was not possible before.It is superior to push enteroscopy,enteroclysis and barium radiography for diagnosing clinically significant SB pathology resulting in IDA.Angioectasia is one of the commonest lesions seen on the CE in elderly with IDA.The diagnostic yield of CE for IDA progressively increases with advancing age,and is highest among patients over 85 years of age.Balloon assisted enteroscopy is used to treat the lesions seen on CE.CE has some limitations mainly lack of therapeutic capability,inability to provide precise location of the lesion and false positive results.Overall CE is a very safe and effective procedure for the evaluation of IDA in elderly.

A guide to diagnosis of iron deficiency and iron deficiency anemia in digestive diseases

Iron deficiency （ID）, with or without anemia, is often caused by digestive diseases and should always be investigated, except in very specific situations, as its causes could be serious diseases, such as cancer. Diagnosis of ID is not always easy. Low serum levels of ferritin or transferrin saturation, imply a situation of absolute or functional ID. It is sometimes difficult to differentiate ID anemia from anemia of chronic diseases, which can coexist. In this case, other parameters, such as soluble transferrin receptor activity can be very useful. After an initial evaluation by clinical history, urine analysis, and serological tests for celiac disease, gastroscopy and colonoscopy are the key diagnostic tools for investigating the origin of ID, and will detect the most important and prevalent diseases. If both tests are normal and anemia is not severe, treatment with oral iron can be indicated, along with stopping any treatment with non-steroidal anti-inflammatory drugs. In the absence of response to oral iron, or if the anemia is severe or clinical suspicion of important disease persists, we must insist on diagnostic evaluation. Repeat endoscopic studies should be considered in many cases and if both still show normal results, investigating the small bowel must be considered. The main techniques in this case are capsule endoscopy, followed by

Anemia and iron deficiency in gastrointestinal and liver conditions

Iron deficiency anemia(IDA) is associated with a number of pathological gastrointestinal conditions other than inflammatory bowel disease, and also with liver disorders. Different factors such as chronic bleeding, malabsorption and inflammation may contribute to IDA. Although patients with symptoms of anemia are frequently referred to gastroenterologists, the approach to diagnosis and selection of treatment as well as follow-up measures is not standardized and suboptimal. Iron deficiency, even without anemia, can substantially impact physical and cognitive function and reduce quality of life. Therefore, regular iron status assessment and awareness of the clinical consequences of impaired iron status are critical. While the range of options for treatment of IDA is increasing due to the availability of effective and well-tolerated parenteral iron preparations, a comprehensive overview of IDA and its therapy in patients with gastrointestinal conditions is currently lacking. Furthermore, definitions and assessment of iron status lack harmonization and there is a paucity of expert guidelines on this topic. This review summarizes current thinking concerning IDA as a common co-morbidity in specific gastrointestinal and liver disorders, and thus encourages a more unified treatment approach to anemia and iron deficiency, while offering gastroenterologists guidance on treatment options for IDA in everyday clinical practice.

Effects of H pylori therapy on erythrocytic and iron parameters in iron deficiency anemia patients with H pylori-positive chronic gastristis

AIM： To elucidate the influences of Hpylori infection on oral iron treatment for iron deficiency anemia （IDA）.METHODS： A total of 86 patients were divided into two groups： group A, receiving ferrous succinate combined with triple therapy for H pylori eradication, and group B （control）, treated with ferrous succinate only. During treatment of IDA, dynamic changes in hemoglobin （Hb） level, mean corpuscular volume （MCV）, mean corpuscular hemoglobin （MCH）, serum iron （SI）, and serum ferritin （SF） were compared between the groups.RESULTS： Hb was slightly higher in group A at d 14 alter the start of triple therapy for H pylori eradication （P 〉 0.05）. After the therapy, the increase of Hb in group A became significantly faster than that in group B （P 〈 0.05）. At d 56, the mean Hb in group A returned to the normal level, however, in group B, it was lower than that in group A （P 〈 0.05） although it had also increased compared with that before oral iron treatment. The MCV and MCH in group A recovered to the normal level, and were much higher than those in group B （P 〈 0.05） at d 21. In Group B, the MCV and MCH remained at lower than normal levels until d 42 alter the start of therapy. And then, they reached a plateau in both groups and the differences disappeared （P 〉 0.05）. The SF in group A was higher than that in group B （P 〈 0.05） 28 d alter the treatment and its improvement was quicker in group A （P 〈 0.05）, and the difference between the two groups was even more significant （P 〈 0.01） at d 56. The SI in group A was higher than that in group B （P 〈 0.05） at d 14 and this persisted until d 56 when the follow-up of this research was finished.CONCLUSION： Treatment of H pylori can enhance the efficacy of ferrous succinate therapy in IDA patients with Hpylori-positive chronic gastritis.

Treatment of iron deficiency anemia associated with gastrointestinal tract diseases

The gastrointestinal (GI) tract is a common site of bleeding that may lead to iron deficiency anemia (IDA). Treatment of IDA depends on severity and acuity of patients’ signs and symptoms. While red blood cell transfusions may be required in hemodynamically unstable patients, transfusions should be avoided in chronically anemic patients due to their potential side effects and cost. Iron studies need to be performed after episodes of GI bleeding and stores need to be replenished before anemia develops. Oral iron preparations are efficacious but poorly tolerated due to non-absorbed iron-mediated GI side effects. However, oral iron dose may be reduced with no effect on its efficacy while decreasing side effects and patient discontinuation rates. Parenteral iron therapy replenishes iron stores quicker and is better tolerated than oral therapy. Serious hypersensitive reactions are very rare with new intravenous preparations. While data on worsening of inflammatory bowel disease (IBD) activity by oral iron therapy are not conclusive, parenteral iron therapy still seems to be advantageous in the treatment of IDA in patients with IBD, because oral iron may not be sufficient to overcome the chronic blood loss and GI side effects of oral iron which may mimic IBD exacerbation. Finally, we believe the choice of oral vs parenteral iron therapy in patients with IBD should primarily depend on acuity and severity of patients’ signs and symptoms.

Electrophysiological changes of autonomic cells in left ventricular outflow tract in guinea pigs with iron deficiency anemia complicated with chronic heart failure

Objective: To investigate the electrophysiological changes of autonomic cells in left ventricular outflow tract in guinea pigs with iron deficiency anemia complicated with chronic heart failure.Methods: Guinea pigs model of iron deficiency anemia complicated with chronic heart failure in 10 guinea pigs of the experimental group was made by feeding a low iron diet,pure water and subcutaneous injection of isoproterenol. The control group consisting of 11 guinea pigs was given normal food, normal water and injected with normal saline. The left ventricular outflow tract model specimen was also prepared. The standard microelectrode technique was used to observe electrophysiological changes of autonomic cells in the outflow tract of left ventricular heart failure complicated with iron deficiency anemia in guinea pig model. The indicators of observation were maximal diastolic potential, action potential amplitude, 0 phase maximal depolarization velocity, 4 phase automatic depolarization velocity, repolarization 50% and 90%, and spontaneous discharge frequency.Results: Compared with the control group, 4 phase automatic depolarization velocity,spontaneous discharge frequency and 0 phase maximal depolarization velocity decreased significantly(P < 0.01) and action potential amplitude reduced(P < 0.01) in model group. Moreover, repolarization 50% and 90% increased(P < 0.01).Conclusions: There are electrophysiological abnormalities of the left ventricular outflow tract in guinea pigs with iron deficiency anemia complicated with heart failure.

Gluten sensitive enteropathy in patients with iron deficiency anemia of unknown origin

AIM: To determine the prevalence of gluten sensitive enteropathy (GSE) in a large group of patients with iron deficiency anemia (IDA) of obscure origin. METHODS: In this cross-sectional study, patients with IDA of obscure origin were screened for GSE. Anti- endomysial antibody (EMA) and tissue transglutamin- ase antibody (tTG) levels were evaluated and duodenal biopsies were taken and scored according to the Marsh classification. The diagnosis of GSE was based on a positive serological test and abnormal duodenal histol- ogy. Gluten free diet (GFD) was advised for all the GSE patients. RESULTS: Of the 4120 IDA patients referred to our Hematology departments, 206 (95 male) patients were found to have IDA of obscure origin. Thirty out of 206 patients (14.6%) had GSE. The mean age of GSE pa- tients was 34.6 ± 17.03 (range 10-72 years). The female to male ratio was 1.3:1. Sixteen patients had Marsh 3,12 had Marsh 2, and 2 had Marsh 1 lesions. The sever- ity of anemia was in parallel with the severity of duode- nal lesions. Twenty-two GSE patients (73.3%) had no gastrointestinal symptoms. Fourteen GSE patients who adhered to GFD without receiving iron supplementation agreed to undergo follow up visits. After 6 mo of GFD, their mean hemoglobin levels (Hb) increased from 9.9 ± 1.6 to 12.8 ± 1.0 g/dL (P < 0.01). Interestingly, in 6 out of 14 patients who had Marsh 1/2 lesions (e.g. no villous atrophy) on duodenal biopsy, mean Hb increased from 11.0 ± 1.1 to 13.1 ± 1.0 g/dL (P < 0.01) while they did not receive any iron supplementation. CONCLUSION: There is a high prevalence (e.g. 14.6%) of GSE in patients with IDA of obscure origin. Gluten free diet can improve anemia in GSE patients who have mild duodenal lesions without villous atrophy.

Autoimmune gastritis presenting as iron deficiency anemia in childhood

AIM: To characterize clinical, laboratorial, and histological profile of pediatric autoimmune gastritis in the setting of unexplained iron deficiency anemia investigation.

Iron deficiency anemia in inflammatory bowel disease

Anemia is a common extraintestinal manifestation of inflammatory bowel disease(IBD) and is frequently overlooked as a complication. Patients with IBD are commonly found to have iron deficiency anemia(IDA) secondary to chronic blood loss, and impaired iron absorption due to tissue inflammation. Patients with iron deficiency may not always manifest with signs and symptoms; so, hemoglobin levels in patients with IBD must be regularly monitored for earlier detection of anemia. IDA in IBD is associated with poor quality of life, necessitating prompt diagnosis and appropriate treatment. IDA is often associated with inflammation in patients with IBD. Thus, commonly used labora-tory parameters are inadequate to diagnose IDA, and newer iron indices, such as reticulocyte hemoglobin content or percentage of hypochromic red cells or zinc protoporphyrin, are required to differentiate IDA from anemia of chronic disease. Oral iron preparations are available and are used in patients with mild disease activity. These preparations are inexpensive and con-venient, but can produce gastrointestinal side effects, such as abdominal pain and diarrhea, that limit their use and patient compliance. These preparations are partly absorbed due to inflammation. Non-absorbed iron can be toxic and worsen IBD disease activity. Although cost-effective intravenous iron formulations are widely available and have improved safety profiles, physicians are reluctant to use them. We present a review of the pathophysiologic mechanisms of IDA in IBD, improved diagnostic and therapeutic strategies, efficacy, and safety of iron replacement in IBD.

γ⁃Fe2O3@carboxymethyl Cellulose as Potential Oral Nanomedicine for Iron Deficiency Anemia Treatment on Rats

Oral iron supplements such as ferrous iron salts are major treatment agents for iron deficiency anemia(IDA)due to the convenience of large dose administration and good patient compliance.However,the gastrointestinal adverse impact caused by Fe2+stimulus and low bioavailability severely impedes its therapeutic effects.In recent years,it has been found that nano iron⁃based nanoparticles with high surface⁃to⁃volume ratio and low iron ion leakage can alleviate the toxic effect and improve the gastrointestinal absorbance.For further clinical development,nano materials need to meet the pharmaceutical quality demand.Carboxymethyl cellulose(CMC)is a significant pharmaceutical ingredient applied in approved drug formulations,and polyglucosorbitol carboxymethylether(PSC)has been utilized in iron⁃based nanomedicine ferumoxytol synthesis,both of which can be firmly anchored on iron oxide by carboxyl chelation.In this work,iron oxide nanoparticles(NPs)modified with CMC were designed and synthesized,and the structure composition and physicochemical properties were distinctly characterized.Oral supplement effects on rat IDA were investigated and compared with other recently reported iron supplements including NPs modified with PSC.Results show that the oral nano iron supplement achieved the recovery of hemoglobin and serum iron level in only two weeks with high safety.The nano iron oxide modified with pharmaceutical excipients provides new potential approach for oral iron supplement available in clinics.

Iron deficiency anemia in celiac disease

Iron is an important micronutrient that may be depleted in celiac disease. Iron deficiency and anemia may complicate well-established celiac disease,but may also be the presenting clinical feature in the absence of diarrhea or weight loss. If iron deficiency anemia occurs,it should be thoroughly evaluated,even if celiac disease has been defined since other superimposed causes of iron deficiency anemia may be present. Most often,impaired duodenal mucosal uptake of iron is evident since surface absorptive area in the duodenum is reduced,in large part,because celiac disease is an immune-mediated disorder largely focused in the proximal small intestinal mucosa. Some studies have also suggested that blood loss may occur in celiac disease,sometimes from superimposed small intestinal disorders,including ulceration or neoplastic diseases,particularly lymphoma. In addition,other associated gastric or colonic disorders may be responsible for blood loss. Rarely,an immune-mediated hemolytic disorder with increased urine iron loss may occur that may respond to a gluten-free diet. Reduced expression of different regulatory proteins critical in iron uptake has also been defined in the presence and absence of anemia. Finally,other rare causes of microcytic anemia may occur in celiac disease,including a sideroblastic form of anemia reported to have responded to a gluten-free diet.