Recognize chronic inflammatory conditions that affect the interpretation of laboratory markers of iron status, Identify patients most likely to benefit from iron supplementation using ferritin and transferrin saturation, Understand risks and benefits of oral and IV iron preparations. ALT, alanine transferase; AWP, average wholesale price (reported on UpToDate.com; last accessed 25 September 2020); GGT, -glutamyl transferase; LMW, low-molecular-weight; MRI, magnetic resonance imaging; NS, normal saline (0.9% sodium chloride); USD, US dollars. The diagnosis of iron deficiency anemia is confirmed by the findings of low iron stores and a hemoglobin level two standard deviations below normal. The predictive value of baseline CRP in terms of Hb response was assessed after retrospective stratification of the study population into a high-CRP and a low-CRP population. Sharma N, Begum J, Eksteen B, Elagib A, et al. INTRODUCTION. This study investigated whether systemic inflammation at initiation of treatment (assessed by C-reactive protein [CRP] and interleukin-6 [IL-6] measurements) predicts response to iron therapy. Hemolytic anemia is defined as anemia due to a shortened survival of circulating red blood cells (RBCs) due to their premature destruction. Iron deficiency anemia . The study lacked longer follow-up with prolonged iron administration and assessment of hematological response. Sharma N, Laftah AH, Brookes MJ, Cooper B, Iqbal T, Tselepis C. A role for tumour necrosis factor alpha in human small bowel iron transport. government site. This is the largest study showing an impact of systemic inflammation on iron absorption in anemic IBD patients. Parenteral iron still enjoys the bad reputation of causing severe allergic reactions, mostly because of frequent reactions to high-molecular-weight iron dextran, which has been discontinued, but some manufacturers still recommend a test dose for some formulations (Table 3). Iron deficiency anemia (IDA) is the most commonly recognized type of anemia in . Kleber Yotsumoto Fertrin; Diagnosis and management of iron deficiency in chronic inflammatory conditions (CIC): is too little iron making your patient sick?. Patients can also call 8-1-1 to speak . Iron release is so restricted that the decrease in serum iron still lowers TSAT despite low TIBC. Conflict-of-interest disclosure: The author declares no competing financial interests. Statistical significance was assumed to be at p<0.05. Their opposing reactions to low and high intracellular iron render ferritin levels of limited help in distinguishing between isolated FID and the association between absolute ID and FID.4 Other biomarkers, such as soluble transferrin receptor, the soluble transferrin receptor/log ferritin index, and hepcidin levels, have been regarded as improving the ability to detect absolute ID in combination with FID, but there is a lack of standardization and limited availability for broader use.11. In oral iron-treated patients, a considerable trend toward lower Hb response was observed in the high- versus low-IL-6 groups, but differences did not quite reach the statistical significance (p<0.07 at weeks 2 and 8; Fig. Jrgen Stein, Email: ed.trufknarf-inu.me@niets.j. Data from a previously published phase III trial were retrospectively analyzed after stratification of patients according to baseline CRP (>4 vs. 4mg/L) and IL-6 (>6 vs. 6pg/mL) levels. C-reactive protein (CRP) is widely used as a routine marker of chronic or acute inflammation [7]. A total of 196 patients were evaluated (oral iron: n=60; i.v. de Silva AD, Tsironi E, Feakins RM, Rampton DS. The correlation between the degree of inflammation and response to oral or i.v. Gasche C, Berstad A, Befrits R, Beglinger C, et al. The American Academy of Pediatrics recommends universal hemoglobin screening and evaluation of risk factors for iron deficiency anemia in all children at one year of age.16 Risk factors include low birth weight, history of prematurity, exposure to lead, exclusive breastfeeding beyond four months of life, and weaning to whole milk and complementary foods without iron-fortified foods.16 The Centers for Disease Control and Prevention recommends screening children from low-income or newly immigrated families at nine to 12 months of age, and consideration of screening for preterm and low-birth-weight infants before six months of age if they are not given iron-fortified formula.14 The U.S. Preventive Services Task Force found insufficient evidence for screening in asymptomatic children six to 12 months of age and does not make recommendations for other ages.4 A meta-analysis showed that infants in whom cord clamping was delayed for up to two minutes after birth had a reduced risk of low iron stores for up to six months.17 Larger randomized studies that include maternal outcomes are needed before delayed cord clamping can be recommended for general practice. official website and that any information you provide is encrypted Choose one of the access methods below or take a look at our subscribe or free trial options. Yellow striped areas represent areas in which iron supplementation may be considered, depending on the CIC; only patients with CKD are likely to benefit from iron supplementation with ferritin <200 g/L and TSAT of 20% to 25%, whereas patients with HF or CKD treated with erythropoiesis-stimulating agents (ESAs) and/or hemodialysis may be considered for iron supplementation if TSAT is <20% and ferritin is up to 500 g/L. Correlations were estimated with Pearsons product-moment method. A week later, she called the office to report that she was still feeling weak and wondered whether her anemia was getting worse. The search included meta-analyses, randomized controlled trials, controlled trials, and reviews. Guidelines often specify certain hemoglobin values as indications to transfuse, but the patient's clinical condition and symptoms are an essential part of deciding whether to transfuse.35 Transfusion is recommended in pregnant women with hemoglobin levels of less than 6 g per dL because of potentially abnormal fetal oxygenation resulting in non-reassuring fetal heart tracings, low amniotic fluid volumes, fetal cerebral vasodilation, and fetal death.15 If transfusion is performed, two units of packed red blood cells should be given, then the clinical situation should be reassessed to guide further treatment.35. CIC cause hepcidin elevation and may preclude GI absorption. National Library of Medicine iron-treated patients, no significant differences between the high- and low-IL-6 groups were observed (overall population and CD/UC subpopulations; Fig. BMID is found in patients with a ferritin range between 30 and 200 g/dL and TSAT between 10% and 20%. Schroder O, Mickisch O, Seidler U, de WA, et al. In patients with HF, TSAT >20% essentially excluded the possibility of BMID, regardless of ferritin levels.23 In patients with nondialysis CKD (ndCKD) who underwent BM evaluation, TSAT below 20% had only 50% sensitivity but 83% specificity to detect BMID, and the specificity for BMID improved to 98% if associated with a ferritin level <100 g/L, with a reduction in sensitivity to 33%. Current guidelines recommend empiric treatment in children up to two years of age and in pregnant women with iron deficiency anemia; however, if the hemoglobin level does not increase by 1 g per dL (10 g per L) after one month of therapy in children or does not improve in pregnant women, further evaluation may be indicated.4,15,16 In pregnant patients, poor compliance or intolerance should be considered, and parenteral iron may produce a better response.15, The evaluation should begin with a thorough history and physical examination to help identify the cause of iron deficiency. Fe, elemental iron; LR, label recommendation. The study population consisted of patients with either CD or UC, who had iron deficiency anemia (defined by Hb11g/dL and TSAT<20% or serum ferritin<100ng/mL). For children at low risk for acute inflammation, concurrent measurement of CRP may not be necessary. Very high levels ( above 200 mg/L) result from bacterial infections, burns and severe chronic conditions. 1-10%: hypophosphatemia, skin rash, nausea; Previously iron isomaltoside; verification of phosphate levels is recommended for repeated infusions. Our results suggest that CRP may be useful to identify IBD patients who can benefit from first-line treatment with i.v. By contrast, an iron saturation <5% and an elevated . All Rights Reserved. FOIA Nevertheless, in clinical practice a course of oral iron therapy is often used as first-line treatment for anemic patients with IBD. In ID, iron stores are progressively exhausted before red cell morphology of hemoglobin levels are affected, and patients may experience early symptoms such as fatigue, reduced cognitive performance, and exercise intolerance. The diagnosis of iron deficiency anemia is confirmed by the. In clinical practice, many patients receive initial treatment with iron tablets although intravenous (i.v.) in a patient without chronic disease, active inflammation, or malignancy, C-reactive protein (CRP) can help support the diagnosis of an inflammatory process. Among oral iron-treated patients, those with high baseline CRP had a significantly smaller mean Hb increase than those with low baseline CRP at follow-up visits on week 2, 4, and 8 (n=60; Fig. If hemoglobin and red blood cell indices remain normal, one additional complete blood count should be obtained 12 months later. Refer to Associated Documents for recommended daily intake values, and foods high in iron. Further evaluation should be based on risk factors (Figure 2).10,15,1721, Excessive menstruation is a common cause of iron deficiency anemia in premenopausal women in developed countries; however, a GI source (particularly erosive lesions in the stomach or esophagus) is present in 6 to 30 percent of cases.20,22,23 If the gynecologic workup is negative and the patient does not respond to iron therapy, endoscopy should be performed to exclude an occult GI source.20,22,23, Excessive or irregular menstrual bleeding affects 9 to 14 percent of all women and can lead to varying degrees of iron deficiency anemia.24 Etiologies include thyroid disease, uncontrolled diabetes mellitus, polycystic ovary syndrome, coagulopathies, uterine fibroids, endometrial hyperplasia, hyperprolactinemia, and use of antipsychotics or antiepileptics. Serum ferritin concentrations for the assessment of iron status and iron deficiency in populations, Laboratory diagnosis of iron-deficiency anemia: an overview, New diagnostic tools for delineating iron status, Discordance between erythrocyte sedimentation rate and C-reactive protein measurements: clinical significance, Properties of four acute phase proteins: C-reactive protein, serum amyloid A protein, alpha 1-acid glycoprotein, and fibrinogen, Quantitative data on the magnitude of the systemic inflammatory response and its relationship with serum measures of iron status, Assessment of iron status in settings of inflammation: challenges and potential approaches, Adjusting ferritin concentrations for inflammation: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project, Regression correction equation to adjust serum iron and ferritin concentrations based on C-reactive protein and albumin in patients receiving primary and secondary care, Are current serum and plasma ferritin cut-offs for iron deficiency and overload accurate and reflecting iron status? Another study, a retrospective subanalysis from a phase III trial, found that a high baseline hepcidin level (>20ng/mL) could predict reduced responsiveness to oral iron in anemic patients with chronic kidney disease (n=240) [21]. Thomas C, Kobold U, Thomas L. Serum hepcidin-25 in comparison to biochemical markers and hematological indices for the differentiation of iron-restricted . Values consistent with iron deficiency include a low serum iron level, low transferrin saturation, and a high total iron-binding capacity.2, Soluble transferrin receptor and erythrocyte protoporphyrin testing, or bone marrow biopsy can be considered if the diagnosis remains unclear.2 The soluble transferrin receptor level is an indirect measure of erythropoiesis and is increased in patients with iron deficiency anemia.8 Another benefit of this test is that the soluble transferrin receptor level is unaffected by inflammatory states and can help identify concomitant iron deficiency anemia in patients with anemia of chronic disease.12 Erythrocyte protoporphyrin is a heme precursor and accumulates in the absence of adequate iron stores.11 If other tests are indeterminate and suspicion for iron deficiency anemia persists, the absence of stainable iron in a bone marrow biopsy is considered the diagnostic standard.2, Asymptomatic men and postmenopausal women should not be screened for iron deficiency anemia. Ferritin is a blood protein that contains iron. The World Health Organization (WHO) defines anemia as hemoglobin <13 g/dL and <12 g/dL in adult men and nonpregnant women, respectively,1 a well-known trigger for an investigation of ID. Laftah AH, Sharma N, Brookes MJ, McKie AT, et al. Low transferrin saturation (TSAT), calculated by serum iron divided by total iron-binding capacity (TIBC), indicates iron deficiency. Less commonly, very high platelet levels may cause bleeding. Among iron tablet-treated patients, Hb increase was significantly smaller in the high- versus low-CRP subgroup (1.1 vs. 2.0, 2.3 vs. 3.1, and 3.0 vs. 4.0g/dL at weeks 2, 4, and 8, respectively; all p<0.05). Bregman DB, Morris D, Koch TA, He A, Goodnough LT. Hepcidin levels predict nonresponsiveness to oral iron therapy in patients with iron deficiency anemia. Iron depletion occurs commonly and is related to associations among blood loss, low dietary iron intake, and malabsorption. Overall, validation of the current findings in a larger patient sample is needed, including the investigation of potential differences in the predictive power for CD and UC patients, before clinical recommendations can be made. Diagnosis and management of iron deficiency anemia in patients with IBD. Skin discoloration from extravasation is also a possible complication and patients should be informed of that particular risk. As a library, NLM provides access to scientific literature. Burning pain in the hands or feet. Patients were stratified by baseline IL-6 levels into a high-IL-6 (>6pg/mL; n=95) and a low-IL-6 (6pg/mL; n=95) groups, and responsiveness to iron supplementation (Hb change from baseline) was compared. The sensitivity of computed tomographic colonography for lesions larger than 1 cm is greater than 90 percent.7 The use of barium enema is less reliable, but may be of use if colonoscopy or computed tomographic colonography is not available. iron-treated patients (at week 8) needs to be evaluated. Pathways for the regulation of hepcidin expression in anemia of chronic disease and iron deficiency anemia in vivo. Wiesenthal M, Dignass A, Hartmann F, Iqbal T, Stein J. Serum hepcidin levels predict intestinal iron absorption in IBD patients. Baseline measurements of CRP and IL-6 were available [15]. Guidelines on the diagnosis and management of iron deficiency and anemia in inflammatory bowel diseases. Similarly, the median baseline IL-6 value of the study population (6pg/mL) was used for stratification into a high-IL-6 (>6pg/mL) and low-IL-6 (6 pg/mL) group. Iron deficiency is the most common nutritional disorder worldwide and accounts for approximately one-half of anemia cases. 1. Impaired intestinal iron absorption in Crohns disease correlates with disease activity and markers of inflammation. Fillet G, Beguin Y, Baldelli L. Model of reticuloendothelial iron metabolism in humans: abnormal behavior in idiopathic hemochromatosis and in inflammation. Differential ferritin expression is associated with iron deficiency in coeliac disease. Stefanie Kulnigg-Dabsch, Email: ta.ca.neiwinudem@hcsbad.einafets. ?accessibility.screen-reader.external-link_en_US?. Response to i.v. Overt inflammation with high ESR and CRP levels has usually been found in active autoimmune disorders (eg, Stills disease, rheumatoid arthritis, and inflammatory bowel disorders [IBDs]) and in chronic infections (eg, tuberculosis and chronic osteomyelitis). Patient information: See related handout on iron deficiency anemia, written by the authors of this article. This cutoff is very close to the 5mg/L cutoff which is commonly used in clinical practice to identify the presence of inflammation. The guideline may not apply to all patients with chronic inflammatory conditions (CICs), such as obesity, chronic kidney disease (CKD), liver disease, and heart failure (HF), in whom an increase in CRP is frequently absent, or where AGP measurements are not routinely available. A 56-year-old woman was referred for evaluation of anemia. iron (ferric carboxymaltose). Poor management of anemia can significantly affect the quality of life and lead to an increase in hospitalization rates and associated medical costs [2, 3]. The results of this study suggest that patients with IBD and IDA, who have elevated CRP at initiation of treatment, may benefit from first-line treatment with i.v. When symptoms occur, they're often related to blood clots. Iron supplementation is recommended in all types of IBD-associated anemia where iron deficiency is present [2, 3, 9]. Correspondence Kleber Yotsumoto Fertrin, University of Washington, 825 Eastlake Ave, E MS CE3-300, Seattle, WA 98109; e-mail: kleber@uw.edu. Based on the data from this relatively small patient group, patients with high CRP levels take longer to respond to oral iron but eventually reach similar responses at 3months. Accessibility abnormally high or low. A systematic review, Failure of serum ferritin levels to predict bone-marrow iron content after intravenous iron-dextran therapy, Serum ferritin level remains a reliable marker of bone marrow iron stores evaluated by histomorphometry in hemodialysis patients, A possible role for hepcidin in the detection of iron deficiency in severely anaemic HIV-infected patients in Malawi, Definition of iron deficiency based on the gold standard of bone marrow iron staining in heart failure patients, Bone marrow iron, iron indices, and the response to intravenous iron in patients with non-dialysis-dependent CKD, Bone marrow iron distribution, hepcidin, and ferroportin expression in renal anemia, Iron absorption from supplements is greater with alternate day than with consecutive day dosing in iron-deficient anemic women, Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials, Novel oral iron therapies for iron deficiency anemia in chronic kidney disease, Hypophosphatemia: an evidence-based approach to its clinical consequences and management, Iatrogenic iron overload in dialysis patients at the beginning of the 21st century, Chapter 2: Use of iron to treat anemia in CKD, Intravenous iron in patients undergoing maintenance hemodialysis [published correction appears in, Safety and efficacy of rapidly administered (one hour) one gram of low molecular weight iron dextran (INFeD) for the treatment of iron deficient anemia, Iron absorption and serum ferritin in chronic inflammatory bowel disease, Serum ferritin and bone marrow iron stores. Screening serology for celiac disease should be considered for all adults with iron deficiency anemia. Her rheumatologist was concerned that the patients anemia was too severe to be explained by her autoimmune disease, which was under control, or by her comorbidities and requested a hematologists opinion. Electrophoresis The antibody produced by myeloma cells is abnormal because it is monoclonal (all the exact same ). It can signal flare-ups of inflammatory diseases such as rheumatoid arthritis, lupus, and vasculitis. A moderate elevation may be due to acute inflammation from an infection or chronic . Those with elevated levels are at an increased risk for diabetes, hypertension and cardiovascular disease. ferric carboxymaltose (FCM) with oral ferrous sulfate (FS) in IBD patients, were retrospectively analyzed. Its indication in clinical practice by itself has become rare with the ease of the use of ferritin, but it may occasionally prove useful in patients who undergo BM sampling for other reasons. Change in C-Reactive . A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. Moreover, other mechanisms put patients with CICs at higher risk of ID and underscore the need to make a correct diagnosis despite interference in iron parameters (Table 1). A more practical approach is to recheck the patient periodically; no further follow-up is necessary if the patient is asymptomatic and the hematocrit level remains normal.7, There is no universally accepted threshold for transfusing packed red blood cells in patients with iron deficiency anemia. 1e, f). sharing sensitive information, make sure youre on a federal Ferritin is an acute-phase protein and its serum levels are elevated during inflammation, reflecting the inflammatory state rather than iron stores. iron was mainly independent of inflammation. C-reactive protein (CRP) is widely used as a routine marker of chronic or acute inflammation [7]. An official website of the United States government. Background: C-reactive protein (CRP) is a widely used inflammatory marker. Prediction of response to iron sucrose in inflammatory bowel disease-associated anemia. Low-molecular-weight iron deficiency, iron sucrose, and ferric gluconate may require several shorter infusions, whereas the remainder have become increasingly popular because of the lower number of visits required to administer high-dose infusions, despite the higher cost of the medication. Moreover, i.v. Hepcidin expression results in a reduction in the uptake of iron from the duodenum and a reduction in the ability of the body to utilize sufficient iron for effective erythropoiesisalso called functional iron deficiency [5, 6]. The World Health Organization (WHO) defines anemia as hemoglobin <13 g/dL and <12 g/dL in adult men and nonpregnant women, respectively, 1 a well-known trigger for an investigation of ID. Data from a randomized, multicenter, controlled phase III trial [15], which compared the efficacy and safety of i.v. Current status of the measurement of blood hepcidin levels in chronic kidney disease. . Baseline CRP and IL-6 levels were independent of patients initial Hb levels and iron status (serum ferritin and TSAT; all p>0.05). Also at week 12, Hb increment tended to be smaller in the high- versus low-CRP group, but the difference did not reach statistical significance. The study was conducted in accordance with good clinical practice guidelines and the Declaration of Helsinki, and was approved by the ethics committee at each site. 1000-mg single dose in 100-500 mL NS with a final concentration >1 mg iron/mL, infused over >20 min. Other indications for parenteral iron include GI tract resection (including bariatric surgery), prolonged use of inhibitors of iron absorption (eg, proton pump inhibitors), and GI intolerance to oral iron (reported in 30% to 70% of patients). Low-grade inflammation in a CIC is enough to disrupt iron metabolism by increasing hepcidin, but does not necessarily correlate with inflammatory markers. Long-term use of aspirin or other nonsteroidal anti-inflammatory drugs, Cameron ulcer (i.e., ulcer in large hiatal hernia), Based on weight and amount of desired change in hemoglobin, One to three tablets two or three times per day. Iron restriction eventually leads to the anemia of inflammation. Characteristics and side effects of most commonly available oral iron supplements. Oral treatment is cost effective, easily available, and should always be considered. Relationship of functional and antigenic interleukin 6 to disease activity in inflammatory bowel disease. Copyright 2023 American Academy of Family Physicians. Search for other works by this author on: Vitamin and Mineral Nutrition Information System (WHO/NMH/NHD/MNM/11.1). 2df). Reinisch W, Staun M, Tandon RK, Altorjay I, et al. Figure 3 shows TSAT and ferritin levels found in patients with different CICs, with and without BMID. Assessment of iron stores using ferritin and TSAT in CICs. The study population consisted of patients with Crohns disease or ulcerative colitis and IDA (Hb110g/L and TSAT<20% or serum ferritin<100ng/mL), randomized to either oral (ferrous sulfate) or i.v. Hematuria and epistaxis should be included in the inquiry because patients frequently fail to mention them. Wiesenthal M, Dignass A, Hartmann F, Stein J. Iron is an essential mineral needed to make red blood cells, and low amounts can lead to anemia, causing headaches, pale skin, fatigue, and other symptoms. An endometrial biopsy should be considered in women 35 years and younger who have conditions that could lead to unopposed estrogen exposure, in women older than 35 years who have suspected anovulatory bleeding, and in women with abnormal uterine bleeding that does not respond to medical therapy.25, In men and postmenopausal women, GI sources of bleeding should be excluded. is of special relevance to Fe biofortifcation as it provides the population with a regular high consumption of contaminant soil Fe due to the traditional threshing procedure under the hooves of the cattle.
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