Differences were less pronounced with stratification according to baseline IL-6. The history should focus on potential etiologies and may include questions about diet, gastrointestinal (GI) symptoms, history of pica or pagophagia (i.e., compulsive consumption of ice), signs of blood loss (e.g., epistaxis, menorrhagia, melena, hematuria, hematemesis), surgical history (e.g., gastric bypass), and family history of GI malignancy. High levels of 40-200 mg/L ?will occur in active inflammation or chronic bacterial infection. SKD received speaker honoraria from Vifor International. Serum protein electrophoresis (SPEP) is a test that measures the antibodies in the blood and can find a monoclonal antibody. Kleber Yotsumoto Fertrin; Diagnosis and management of iron deficiency in chronic inflammatory conditions (CIC): is too little iron making your patient sick?. She received an infusion of FCM uneventfully. Impaired intestinal iron absorption in Crohns disease correlates with disease activity and markers of inflammation. Less commonly, very high platelet levels may cause bleeding. It can signal flare-ups of inflammatory diseases such as rheumatoid arthritis, lupus, and vasculitis. Prominent anisocytosis and poikilocytosis, including pencil-shaped RBC forms, on the peripheral smear, tend to favor iron deficiency over ACD. However, the potential of hepcidin as a biomarker is limited, even though it is a more direct measure of iron sequestration than the well-established but unspecific inflammatory marker CRP. In addition to Hb and CRP measurements, the workup for IBD patients should include assessment of serum ferritin and transferrin saturation (TSAT) to accurately diagnose iron deficiency. Response to i.v. Ferrous fumarate (Ferretts, Ferrimin, Hemocyte), 1 tablet every other day (>100 mg Fe per dose). 2a), apart from early response in the CD subpopulation (p<0.05 at week 2; Fig. A growing portfolio is currently available in the United States: low-molecular-weight iron dextran, iron sucrose, ferric gluconate, ferumoxytol, ferric carboxymaltose (FCM), and ferric derisomaltose (previously known as iron isomaltoside; Table 3). Ferritin is an acute-phase protein and its serum levels are elevated during inflammation, reflecting the inflammatory state rather than iron stores. Tumour necrosis factor alpha causes hypoferraemia and reduced intestinal iron absorption in mice. Aapro M, Osterborg A, Gascon P, Ludwig H, Beguin Y. By contrast, an iron saturation <5% and an elevated . 1df). Iron-deficiency anemia can also cause you to feel dizzy or lightheaded. iron was mainly independent of inflammation. Before A week later, she called the office to report that she was still feeling weak and wondered whether her anemia was getting worse. Search date: January 10, 2012. In clinical practice, CRP levels 5 mg/L are usually considered elevated. Received 2014 Oct 9; Accepted 2014 Nov 21. Weiss G, Goodnough LT. Pathways for the regulation of hepcidin expression in anemia of chronic disease and iron deficiency anemia in vivo. abnormally high or low. In absolute ID, mechanisms are activated to replenish iron: low hepcidin production keeps ferroportin on the membranes to facilitate iron absorption, and transferrin is upregulated to increase total iron binding capacity (TIBC) and transport of iron to the tissues. Initial Hb response to oral iron was significantly lower in IBD patients with a high baseline CRP level (>4mg/L), compared to those with low baseline CRPat least for the first 2months of treatment. If you have a Best Practice personal account, your own subscription or have registered for a free trial, log in here: If your hospital, university, trust or other institution provides access to BMJ Best Practice through services such as OpenAthens or Shibboleth, log in via this button: If you have been provided an access code, you can register it here: For any urgent enquiries please contact our customer services team who are ready to help with any problems. Patients should always be investigated for blood loss, such as uterine and GI bleeding. Both ID and FID have hypoferremia but low TIBC, and high ferritin characterizes FID. Other analytical methods utilizing mass spectrometry are not feasible for routine use in a hospital or outpatient setting [23]. Following an inflammatory stimulus, causing, for example, IL6 expression which can directly induce CRP expression in the liver, CRP levels rise rapidly to peak levels of 350400mg/L. 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]. which is commonly affected by CD. 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. In . 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. iron (CD: n=40; UC: n=96). 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. Methods: We collected all patients seen at a university hospital in 2004 with at least one CRP level above 500 mg/l and retrospectively analyzed their electronic files, focusing on patient characteristics, clinical . The underlying cause should be treated, and oral iron therapy can be initiated to replenish iron stores. Supplemental iron may be given initially, followed by further workup if the patient is not responsive to therapy. CRP and IL-6 values were slightly higher in CD versus UC patients, but the differences were statistically not significant (Table1). There is no specific iron-containing preparation recommended to treat ID (Table 2), and evidence in pure ID/IDA supports that a single minimum dose of 60 mg of elemental iron administered on alternate days can be adequate and maximize tolerability,26,28,29 but studies in patients with CIC who are following such a regimen are lacking. In the overall patient population, 46% had a baseline CRP level 5mg/L. The study lacked longer follow-up with prolonged iron administration and assessment of hematological response. In clinical practice, many patients receive initial treatment with iron tablets although intravenous (i.v.) NSAIDs, nonsteroidal anti-inflammatory drugs. 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. In clinical practice, CRP levels 5mg/L are usually considered elevated. >50%: fecal discoloration, abdominal pain, nausea; Ferric polymaltose (Maltofer; not available in the US). Hide glossary Glossary. You have had a history of viral flu. CKD patients suffer from both absolute and functional iron deficiency. Iron deficiency anemia is a common complication of chronic kidney disease (CKD). Differential ferritin expression is associated with iron deficiency in coeliac disease. Patients may be asymptomatic or present with nonspecific symptoms including fatigue, irritability, and dizziness. Recent data suggest that there are also other pro-inflammatory pathways modulating duodenal iron absorption. ID is defined as a health-related condition in which iron availability is insufficient to meet the bodys needs and which can be present with or without anemia,3(p1069) and it is fundamentally recognized that IDA is simply the most advanced stage of ID. 2df). Anemia can have many different causes. See permissionsforcopyrightquestions and/or permission requests. Another common symptom is restless leg syndrome (RLS), which is an unpleasant urge to move the legs during periods of inactivity. 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. In i.v. 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. We also investigated baseline IL-6 levels in our study, and some significant differences between the high- and low-IL-6 groups in terms of Hb response to oral iron could be observed. Patients and physicians should discuss risks and benefits of oral and parenteral iron preparations to make personalized treatment decisions, especially when patients have multiple comorbidities and do not fit the available guidelines. In general, an elevated RDW has been associated with anemia from nutritional deficiencies such B12, folate or iron. A subscription is required to access all the content in Best Practice. CD Crohns disease, Hb hemoglobin, IL-6 interleukin-6, i.v. Patients can also call 8-1-1 to speak . Iron deficiency anemia is diminished red blood cell production due to low iron stores in the body. Conflict-of-interest disclosure: The author declares no competing financial interests. Our results suggest that CRP may be useful to identify IBD patients who can benefit from first-line treatment with i.v. A randomized, open-label, non-inferiority study of intravenous iron isomaltoside 1,000 (Monofer) compared with oral iron for treatment of anemia in IBD (PROCEED). HHS Vulnerability Disclosure, Help Searches were also performed using Essential Evidence Plus, the Cochrane database, the National Guideline Clearinghouse database, the Trip Database, DynaMed, and the Agency for Healthcare Research and Quality evidence reports. Iron deficiency anemia (IDA) is the most commonly recognized type of anemia in . Normal values for CRP range between 0.20 and 6.10 mg/L [8]. Diagnosis of iron deficiency anemia requires laboratory-confirmed evidence of anemia, as well as evidence of low iron stores.4 Anemia is defined as a hemoglobin level two standard deviations below normal for age and sex (Table 1).5, A complete blood count can be helpful to determine the mean corpuscular volume or red blood cell size. Overlap of ID and other disorders, such as chronic liver or kidney disease, may prevent the MCH and MCV from decreasing, and such indices also become unreliable for use in screening for ID in the presence of thalassemia trait, a frequent hereditary anemia. FOIA Data from all FAS patients with available baseline CRP were included for analysis. Statistical significance was assumed to be at p<0.05. >20%: hypotension and muscle cramps in hemodialysis patients; Incidence unknown: hypotension, flushing, headache, urticaria, GI symptoms, anaphylaxis, injection site reaction, myalgia, dyspnea, wheezing, fever. Previously recommended, but currently not on label; >20%: hypotension, vomiting, nausea, headache, diarrhea, injection site reaction, muscle cramps; 1-10%: hypotension, edema, chest pain, hypertension, dizziness, headache, pruritus, rash, diarrhea, nausea, constipation, vomiting, abdominal pain, hypersensitivity reaction, cough, dyspnea, fever. Most IBD patients become iron deficient at some stages of the disease [3, 4]. Despite a ferritin level of 89 g/L (considered normal for healthy individuals), the presence of ferritin <200 g/L, a TSAT <20% in the presence of several CICs (liver disease, controlled rheumatoid arthritis, and stage 3 ndCKD), and hypoproliferative normochromic, normocytic anemia supported a diagnosis of IDA. Thomas C, Kobold U, Thomas L. Serum hepcidin-25 in comparison to biochemical markers and hematological indices for the differentiation of iron-restricted . Hematology Am Soc Hematol Educ Program 2020; 2020 (1): 478486. Screening serology for celiac disease should be considered for all adults with iron deficiency anemia. 1c). Wiesenthal M, Dignass A, Hartmann F, Stein J. Fever (p<0.0001), arthritis (p<0.03) were significantly related and CRP was elevated (p<0.04) in cases with high SLEDAI (severe flare). Evstatiev R, Gasche C. Iron sensing and signalling. 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). Data from a randomized, multicenter, controlled phase III trial [15], which compared the efficacy and safety of i.v. 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. Refer to Associated Documents for recommended daily intake values, and foods high in iron. Incidence unknown: constipation, abdominal pain, diarrhea, muscle cramps. Can iron deficiency cause high CRP? As the test subjects were not anemic, only a single dose of oral iron was administered. 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). 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. Statistical support and medical writing support were funded by Vifor Pharma Ltd. TI received lecture fees from Vifor Pharma Ltd and Shire Pharmaceuticals Inc. JS has received consulting fees and been a member of advisory committees or review panels of Abbott Laboratories, Falk Pharma, Ferring Pharmaceuticals Inc, Fresenius Kabi Ltd, Immundiagnostik AG, MSD, Nycomed, Shire Pharmaceuticals Inc, and Vifor Pharma Ltd. NS has no conflicts of interest to disclose. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. The two most common causes of anemia in IBD patients are absolute iron deficiency and anemia of chronic disease (ACD; also referred to as anemia of chronic inflammation) [1, 3]. In mice treated with the inflammatory cytokine TNF-, reduced iron transport across the duodenal mucosa was shown [18, 19]. Iatrogenic iron overload is another concern in the absence of reliable ferritin levels. (<11 g/dL), normal/enhanced sFtn level (>100 g/L), high level of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and IL-6. National Library of Medicine Based on the available evidence from BMID studies, the map in Figure 4 has been designed to help estimate the adequacy of iron stores and to aid in interpreting ferritin and TSAT in patients with CIC. Lastly, a recently presented investigation from our group has shown that IBD patients with ACD respond differently to oral iron treatment compared to those with IDA [12]. . Recently, a large randomized clinical trial favored the use of a high-dose regimen of 400 mg/mo of iron to lower risk of death and nonfatal cardiovascular events in patients in hemodialysis within a 2-year time frame, but did not report incidence of liver iron overload, so concerns for late effects of excess iron remain.34 If iatrogenic iron overload is suspected, MRI can be used, but different intervals for each iron formulation are recommended before MRI scans, to prevent interference with imaging (Table 3).32 In patients on hemodialysis with confirmed iron overload, the discontinuation of iron infusions has been shown to correct it slowly over several months without the need for iron chelators. Transferrin saturation (TSAT) <6% in combination with low ferritin is diagnostic of ID, but in the presence of inflammation, a seemingly arbitrary TSAT <20% is often used to diagnose ID. One of the functions of an acute-phase reaction is to prevent iron from being scavenged by pathogens. A percentage of hypochromic red cells >6% and a reticulocyte hemoglobin equivalent (CHr or Ret-He) <29 pg, as provided by some modern cell counters, also supports iron-restricted erythropoiesis. Patients were stratified by baseline CRP levels into a high-CRP (>4mg/L; n=96) and a low-CRP (4mg/L; n=100) group, and responsiveness to iron supplementation (Hb change from baseline) was compared. TSAT 20% to 25% is still associated with BMID in CKD, and TSAT <20% may still predict BMID in patients with ferritin up to 500 g/L with HF or CKD treated with ESAs, with or without hemodialysis. iron (ferric carboxymaltose). The diagnosis of iron deficiency anemia is confirmed by the. 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. Prevalence and management of cancer-related anaemia, iron deficiency and the specific role of intravenous iron. C-reactive protein (CRP) is a substance produced by the liver that increases in the presence of inflammation in the body. Intravenous iron sucrose versus oral iron supplementation for the treatment of iron deficiency anemia in patients with inflammatory bowel diseasea randomized, controlled, open-label, multicenter study. Iron deficiency anemia signs and symptoms may include: Extreme fatigue Weakness Pale skin Chest pain, fast heartbeat or shortness of breath Headache, dizziness or lightheadedness Cold hands and feet Inflammation or soreness of your tongue Brittle nails Unusual cravings for non-nutritive substances, such as ice, dirt or starch 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? Not to be confused with high-molecular-weight dextran (discontinued); 4-wk interval recommended before MRI. In addition, gut luminal iron may induce oxidative stress [13] and increase local disease activity in IBD [3, 14]. 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. Erichsen K, Hausken T, Ulvik RJ, Svardal A, Berstad A, Berge RK. CD Crohns disease, CRP C-reactive protein, Hb hemoglobin, i.v. Consider dietitian referral. Shortness of breath and nausea. Correspondence Kleber Yotsumoto Fertrin, University of Washington, 825 Eastlake Ave, E MS CE3-300, Seattle, WA 98109; e-mail: kleber@uw.edu. Iron deficiency anemia (IDA) is the most common acquired anemia and should be the first consideration in a patient with unexplained anemia. Current status of the measurement of blood hepcidin levels in chronic kidney disease. You may notice pale skin and cold hands and feet. Results In total, 2141 participants were included in the analyses (mean age: 74.9 years, 61.5% of women, 26.8% with iron deficiency). in a patient without chronic disease, active inflammation, or malignancy, C-reactive protein (CRP) can help support the diagnosis of an inflammatory process. Studies that reported only ferritin levels are represented by red lines beneath the x-axis that encompass the range, and means are represented by diamonds situated on the lines. iron therapy. Anaemia is defined by the World Health Organization as a Hb level below 120 g/L in non-pregnant females and 130 g/L in males, which is consistent with the definition of anaemia in the National Blood Authority Patient Blood Management Guidelines. Characteristics and side effects of most commonly available oral iron supplements. ?accessibility.screen-reader.external-link_en_US?. BMID is found in patients with a ferritin range between 30 and 200 g/dL and TSAT between 10% and 20%. Chest pain. Schematic representation of the regulation of iron metabolism in absolute ID. . I. The cutoff level for stratification of patients into a high- and a low-CRP subgroup was 4mg/L, based on the median CRP level in the evaluated population. Parenteral therapy may be used in patients who cannot tolerate or absorb oral preparations. IBD patients with ACD had impaired oral iron absorption which correlated with disease activity and inflammatory markers but was independent of disease location and type of IBD (UC or CD). Absolute iron deficiency is defined by severely reduced or absent iron stores, while functional iron deficiency is defined by adequate iron stores but insufficient iron availability for incorporatio Summary and statistical analyses were performed using SAS version 8 or later and R version 3.0.2. A systematic review19 examined 38 studies of BM iron in nonhealthy adults with rheumatoid arthritis, liver disease, hematologic disorders, and other CICs. Her laboratory results showed that her hemoglobin had had a minor increase from 7.9 to 8.2 g/dL, but her phosphate levels were moderately decreased at 1.6 mg/dL. The Biomarkers Reflecting Inflammation and Nutrition Determinants of Anemia (BRINDA) research group found that a regression correction of ferritin using CRP >5 mg/L and AGP >1 g/L increased the prevalence of ID by 3% to 7%, even in countries with a low burden of infection, such as the United States,15,16 and a different regression correction using CRP and albumin increased the prevalence of ID from 7% to 24% in another study.17 Therefore, in areas of widespread inflammation or infection, the 2020 WHO guidelines18 strongly endorse the measurement of CRP and AGP, but make a conditional recommendation to use a ferritin threshold of 70 g/L to define iron deficiency in patients with CRP >5 mg/L or AGP >1 g/L or to implement arithmetic or regression correction of ferritin levels based on those markers. Patients with high baseline CRP achieved a lower Hb response with oral iron therapy. The https:// ensures that you are connecting to the Any condition that elevates . Examples include: Headache. Anemia of chronic disease. iron has been shown to be at least as effective as oral iron in randomized trials, delivering faster response rates and being better tolerated than oral iron [3, 9, 15, 2628].
