Iron deficiency across chronic inflammatory conditions: International expert opinion on definition, diagnosis, and management

Abstract Iron deficiency, even in the absence of anemia, can be debilitating, and exacerbate any underlying chronic disease, leading to increased morbidity and mortality. Iron deficiency is frequently concomitant with chronic inflammatory disease; however, iron deficiency treatment is often overlooked, partially due to the heterogeneity among clinical practice guidelines. In the absence of consistent guidance across chronic heart failure, chronic kidney disease and inflammatory bowel disease, we provide practical recommendations for iron deficiency to treating physicians: definition, diagnosis, and disease‐specific diagnostic algorithms. These recommendations should facilitate appropriate diagnosis and treatment of iron deficiency to improve quality of life and clinical outcomes.

[1]  Paula Esther Moraga-Serrano Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016:A Systematic Analysis for the Global Burden of Disease Study , 2018 .

[2]  T. Hagve,et al.  [Anemia of chronic disease]. , 2017, Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke.

[3]  Gerasimos S Filippatos,et al.  2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. , 2017, Journal of the American College of Cardiology.

[4]  N. Milman,et al.  Ferric carboxymaltose vs. oral iron in the treatment of pregnant women with iron deficiency anemia: an international, open-label, randomized controlled trial (FER-ASAP) , 2017, Journal of perinatal medicine.

[5]  Gerasimos S Filippatos,et al.  2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. , 2017, Journal of cardiac failure.

[6]  H. Kehlet,et al.  International consensus statement on the peri‐operative management of anaemia and iron deficiency , 2017, Anaesthesia.

[7]  B. Michalke,et al.  Oral versus intravenous iron replacement therapy distinctly alters the gut microbiota and metabolome in patients with IBD , 2016, Gut.

[8]  J. M. García-Pinilla,et al.  Consensus Document of the Spanish Society of Cardiology and the Spanish Society of Internal Medicine on the diagnosis and treatment of iron deficiency in heart failure. , 2017 .

[9]  J. M. García-Pinilla,et al.  Consensus Document of the Spanish Society of Cardiology and the Spanish Society of Internal Medicine on the diagnosis and treatment of iron deficiency in heart failure. , 2017, Revista clinica espanola.

[10]  C. Borgna-Pignatti,et al.  Pica as a manifestation of iron deficiency , 2016, Expert review of hematology.

[11]  P. Ponikowski,et al.  [2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure]. , 2016, Kardiologia polska.

[12]  Ashutosh Kumar Singh,et al.  Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015 , 2016, Lancet.

[13]  Volkmar Falk,et al.  2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure , 2016, Revista espanola de cardiologia.

[14]  P. Ponikowski,et al.  Effects of intravenous iron therapy in iron‐deficient patients with systolic heart failure: a meta‐analysis of randomized controlled trials , 2016, European journal of heart failure.

[15]  F. A. Naoum Iron deficiency in cancer patients , 2016, Revista brasileira de hematologia e hemoterapia.

[16]  K. Khan,et al.  Non‐anaemic iron deficiency – a disease looking for recognition of diagnosis: a systematic review , 2016, European journal of haematology.

[17]  W. Paulus,et al.  Restless legs syndrome associated with major diseases , 2016, Neurology.

[18]  R. Saxena,et al.  Randomized controlled trial comparing ferric carboxymaltose and iron sucrose for treatment of iron deficiency anemia due to abnormal uterine bleeding , 2016, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[19]  N. Kassebaum The Global Burden of Anemia. , 2016, Hematology/oncology clinics of North America.

[20]  J. Verdú,et al.  Estado del hierro en la insuficiencia cardiaca crónica: impacto en síntomas, clase funcional y capacidad de ejercicio submáxima , 2016 .

[21]  M. Grau,et al.  Iron Status in Chronic Heart Failure: Impact on Symptoms, Functional Class and Submaximal Exercise Capacity. , 2016, Revista espanola de cardiologia.

[22]  A. Gonçalves,et al.  [Portuguese Consensus on the Diagnosis, Prevention and Treatment of Anaemia in Inflammatory Bowel Disease]. , 2016, Acta medica portuguesa.

[23]  B. Abraham,et al.  The role of ferric carboxymaltose in the treatment of iron deficiency anemia in patients with gastrointestinal disease , 2016, Therapeutic advances in gastroenterology.

[24]  L. Peyrin-Biroulet,et al.  Guidelines on the diagnosis and treatment of iron deficiency across indications: a systematic review. , 2015, The American journal of clinical nutrition.

[25]  P. Ponikowski,et al.  Iron deficiency and cardiovascular disease , 2015, Nature Reviews Cardiology.

[26]  G. Weiss Anemia of Chronic Disorders: New Diagnostic Tools and New Treatment Strategies. , 2015, Seminars in hematology.

[27]  E. Consten,et al.  Multicentre randomized controlled trial comparing ferric(III)carboxymaltose infusion with oral iron supplementation in the treatment of preoperative anaemia in colorectal cancer patients , 2015, BMC Surgery.

[28]  F. Petraglia,et al.  Prevalence of heavy menstrual bleeding and experiences of affected women in a European patient survey , 2015, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[29]  J. Gisbert,et al.  European consensus on the diagnosis and management of iron deficiency and anaemia in inflammatory bowel diseases. , 2015, Journal of Crohn's & colitis.

[30]  I. Macdougall,et al.  Iron therapy for the treatment of iron deficiency in chronic heart failure: intravenous or oral? , 2015, European journal of heart failure.

[31]  F. Aslan,et al.  The Effect of Intravenous Iron Treatment on Quality of Life in Inflammatory Bowel Disease Patients with Nonanemic Iron Deficiency , 2015, Gastroenterology research and practice.

[32]  P. Ponikowski,et al.  Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency† , 2014, European heart journal.

[33]  M. Cowie National Institute for Health and Care Excellence. , 2015, European heart journal.

[34]  A. Cohen-Solal,et al.  Diagnosis and treatment of iron deficiency in patients with heart failure: expert position paper from French cardiologists. , 2014, Archives of cardiovascular diseases.

[35]  A. Low,et al.  Iron deficiency in a multi‐ethnic Asian population with and without heart failure: prevalence, clinical correlates, functional significance and prognosis , 2014, European journal of heart failure.

[36]  M. Greco,et al.  Anaemia from a patient perspective in inflammatory bowel disease: results from the European Federation of Crohn’s and Ulcerative Colitis Association’s online survey , 2014, European journal of gastroenterology & hepatology.

[37]  P. Ponikowski,et al.  Rationale and design of the CONFIRM‐HF study: a double‐blind, randomized, placebo‐controlled study to assess the effects of intravenous ferric carboxymaltose on functional capacity in patients with chronic heart failure and iron deficiency , 2014, ESC heart failure.

[38]  P. Ponikowski,et al.  Iron deficiency and health-related quality of life in chronic heart failure: results from a multicenter European study. , 2014, International journal of cardiology.

[39]  A. Lucendo,et al.  Anemia in inflammatory bowel disease: a neglected issue with relevant effects. , 2014, World journal of gastroenterology.

[40]  Ellen Nolte,et al.  Assessing chronic disease management in European health systems: Concepts and approaches , 2014 .

[41]  G. Keating Ferric Carboxymaltose: A Review of Its Use in Iron Deficiency , 2014, Drugs.

[42]  R. Walker,et al.  KHA‐CARI Guideline: Use of iron in chronic kidney disease patients , 2013, Nephrology.

[43]  A. Kliger,et al.  KDOQI US commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD. , 2013, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[44]  M. Drazner,et al.  2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. , 2013, Journal of the American College of Cardiology.

[45]  T. Ganz Systemic iron homeostasis. , 2013, Physiological reviews.

[46]  F. Prat,et al.  Iron deficiency: from diagnosis to treatment. , 2013, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[47]  Robert T. Means,et al.  Iron deficiency anemia , 2013, Hematology.

[48]  P. Ponikowski,et al.  Intravenous ferric carboxymaltose in iron-deficient chronic heart failure patients with and without anaemia: a subanalysis of the FAIR-HF trial , 2013, European journal of heart failure.

[49]  N. Goldberg Iron deficiency anemia in patients with inflammatory bowel disease , 2013, Clinical and experimental gastroenterology.

[50]  Wim Van Biesen,et al.  Kidney Disease: Improving Global Outcomes guidelines on anaemia management in chronic kidney disease: a European Renal Best Practice position statement. , 2013, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[51]  P. Ponikowski,et al.  Iron deficiency in chronic heart failure: an international pooled analysis. , 2013, American heart journal.

[52]  J. Bauersachs,et al.  Kommentar zu den Leitlinien der Europäischen Gesellschaft für Kardiologie (ESC) zur Diagnostik und Behandlung der akuten und chronischen Herzinsuffizienz , 2013, Der Kardiologe.

[53]  P. Ponikowski,et al.  Iron status in patients with chronic heart failure. , 2013, European heart journal.

[54]  P. Ponikowski,et al.  Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives , 2012, European heart journal.

[55]  J. Adamson,et al.  Notice , 2012, Kidney International Supplements.

[56]  F. Obermeier,et al.  High Prevalence but Insufficient Treatment of Iron-Deficiency Anemia in Patients with Inflammatory Bowel Disease: Results of a Population-Based Cohort , 2012, Gastroenterology research and practice.

[57]  Alissa Westerlund,et al.  Iron deficiency in infancy is associated with altered neural correlates of recognition memory at 10 years. , 2012, The Journal of pediatrics.

[58]  P. Ponikowski,et al.  Beyond the cardiorenal anaemia syndrome: recognizing the role of iron deficiency , 2012, European journal of heart failure.

[59]  L. Leibovici,et al.  Iron supplementation for the treatment of chronic heart failure and iron deficiency: systematic review and meta‐analysis , 2012, European journal of heart failure.

[60]  J. Adamson,et al.  KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease , 2012 .

[61]  M. Aapro,et al.  Anaemia and cancer: oral or intravenous iron? , 2012 .

[62]  G. Keating,et al.  Ferric Carboxymaltose , 2012, Drugs.

[63]  T. Ganz,et al.  The hepcidin-ferroportin system as a therapeutic target in anemias and iron overload disorders. , 2011, Hematology. American Society of Hematology. Education Program.

[64]  P. Ponikowski,et al.  Iron deficiency predicts impaired exercise capacity in patients with systolic chronic heart failure. , 2011, Journal of cardiac failure.

[65]  F. Jamali,et al.  Preoperative anaemia and postoperative outcomes in non-cardiac surgery: a retrospective cohort study , 2011, The Lancet.

[66]  P. Steer Saving Mothers’ Lives. Reviewing maternal deaths to make motherhood safer: 2006–2008 , 2011 .

[67]  P. Poole‐Wilson,et al.  Disordered iron homeostasis in chronic heart failure: prevalence, predictors, and relation to anemia, exercise capacity, and survival. , 2011, Journal of the American College of Cardiology.

[68]  T. Bernklev,et al.  Chronic fatigue is more prevalent in patients with inflammatory bowel disease than in healthy controls , 2011, Inflammatory bowel diseases.

[69]  B. Cherayil The role of iron in the immune response to bacterial infection , 2011, Immunologic research.

[70]  S. Stewart,et al.  Non-pharmacological Management 2011 Update to National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand Guidelines for the Prevention, Detection and Management of Chronic Heart Failure in Australia, 2006 Provides Current Clinical Guidance on Chf , 2022 .

[71]  J. Neilson,et al.  Saving Mothers’ Lives: Reviewing maternal deaths to make motherhood safer: 2006–2008 , 2011, BJOG : an international journal of obstetrics and gynaecology.

[72]  Jian Wang,et al.  Regulation of cellular iron metabolism , 2011, The Biochemical journal.

[73]  P. Geisser,et al.  The Pharmacokinetics and Pharmacodynamics of Iron Preparations , 2011, Pharmaceutics.

[74]  A. Mangione,et al.  A randomized controlled trial comparing intravenous ferric carboxymaltose with oral iron for treatment of iron deficiency anaemia of non-dialysis-dependent chronic kidney disease patients , 2010, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[75]  G. Tsagalis Renal anemia: a nephrologist's view. , 2011, Hippokratia.

[76]  S. Stewart,et al.  Guidelines for the prevention, detection and management of chronic heart failure in Australia, 2006. , 2006 .

[77]  W. Qunibi The efficacy and safety of current intravenous iron preparations for the management of iron-deficiency anaemia: a review , 2010, Arzneimittelforschung.

[78]  P. Ponikowski,et al.  Iron deficiency: an ominous sign in patients with systolic chronic heart failure. , 2010, European heart journal.

[79]  M. Wessling-Resnick,et al.  Iron homeostasis and the inflammatory response. , 2010, Annual review of nutrition.

[80]  R. Garrick A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease , 2010 .

[81]  M. Maeder,et al.  Myocardial and Systemic Iron Depletion in Heart Failure: Implications for Anemia Accompanying Heart Failure , 2010 .

[82]  P. Ponikowski,et al.  Ferric carboxymaltose in patients with heart failure and iron deficiency. , 2009, The New England journal of medicine.

[83]  I. Fraser,et al.  Health-related quality of life and economic burden of abnormal uterine bleeding , 2009 .

[84]  Amanda F. Petrik,et al.  Effect of anaemia on mortality, cardiovascular hospitalizations and end‐stage renal disease among patients with chronic kidney disease , 2009, Nephrology.

[85]  Tomas Ganz,et al.  Iron in innate immunity: starve the invaders. , 2009, Current opinion in immunology.

[86]  I. Cavill,et al.  Ferric Carboxymaltose A Review of its Use in Iron-Deficiency Anaemia , 2009 .

[87]  D. Leaf,et al.  Interpretation and review of health-related quality of life data in CKD patients receiving treatment for anemia. , 2009, Kidney international.

[88]  S. Soroka,et al.  Health-related quality of life and hemoglobin levels in chronic kidney disease patients. , 2009, Clinical journal of the American Society of Nephrology : CJASN.

[89]  Philip McFarlane,et al.  Guidelines for the management of chronic kidney disease , 2008, Canadian Medical Association Journal.

[90]  Jeffery L. Miller,et al.  Individualized treatment for iron-deficiency anemia in adults. , 2008, The American journal of medicine.

[91]  E. McLean,et al.  Worldwide prevalence of anaemia 1993-2005: WHO global database on anaemia. , 2008 .

[92]  A. Berstad,et al.  Guidelines on the diagnosis and management of iron deficiency and anemia in inflammatory bowel diseases. , 2007, Inflammatory bowel diseases.

[93]  P. Duarte,et al.  Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency. , 2007, Journal of the American College of Cardiology.

[94]  T. Dowling Prevalence, etiology, and consequences of anemia and clinical and economic benefits of anemia correction in patients with chronic kidney disease: an overview. , 2007, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[95]  R. Dubois,et al.  Evaluating Health-Related Quality of Life , Work Impairment , and Health-Care Costs and Utilization in Abnormal Uterine Bleeding , 2010 .

[96]  J. Himmelfarb Iron regulation. , 2007, Journal of the American Society of Nephrology : JASN.

[97]  H. Burger,et al.  Normalization of hemoglobin level in patients with chronic kidney disease and anemia. , 2006, The New England journal of medicine.

[98]  Huiman Barnhart,et al.  Correction of anemia with epoetin alfa in chronic kidney disease. , 2006, The New England journal of medicine.

[99]  B. Lozoff,et al.  Double burden of iron deficiency in infancy and low socioeconomic status: a longitudinal analysis of cognitive test scores to age 19 years. , 2006, Archives of pediatrics & adolescent medicine.

[100]  J. Wish Assessing iron status: beyond serum ferritin and transferrin saturation. , 2006, Clinical journal of the American Society of Nephrology : CJASN.

[101]  Farin Kamangar,et al.  Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[102]  K. Kalantar-Zadeh,et al.  Association of anemia with outcomes in men with moderate and severe chronic kidney disease. , 2006, Kidney international.

[103]  S. Corbett,et al.  Effects of changes in hemoglobin level on quality of life and cognitive function in inflammatory bowel disease patients , 2006, Inflammatory bowel diseases.

[104]  S. Aronoff,et al.  The prevalence of anemia in patients with chronic kidney disease , 2004, Current medical research and opinion.

[105]  S. Travis,et al.  Guidelines for the management of inflammatory bowel disease in adults , 2004, Gut.

[106]  I. Cavill,et al.  Iron, anaemia, and inflammatory bowel diseases , 2004, Gut.

[107]  M. Hentze,et al.  Balancing Acts Molecular Control of Mammalian Iron Metabolism , 2004, Cell.

[108]  C. Gullion,et al.  Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. , 2004, Archives of internal medicine.

[109]  P. Hinton,et al.  Tissue iron deficiency without anemia impairs adaptation in endurance capacity after aerobic training in previously untrained women. , 2004, The American journal of clinical nutrition.

[110]  L. Murray-Kolb,et al.  Low hemoglobin level is a risk factor for postpartum depression. , 2003, The Journal of nutrition.

[111]  B. Burnand,et al.  Iron supplementation for unexplained fatigue in non-anaemic women: double blind randomised placebo controlled trial , 2003, BMJ : British Medical Journal.

[112]  W. Hörl Non-erythropoietin-based anaemia management in chronic kidney disease. , 2002, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[113]  P. Hinton,et al.  Marginal iron deficiency without anemia impairs aerobic adaptation among previously untrained women. , 2002, The American journal of clinical nutrition.

[114]  O Jolobe,et al.  Guidelines for the management of iron deficiency anaemia , 2001, Gut.

[115]  J. Haas,et al.  Iron-Deficiency Anemia: Reexamining the Nature and Magnitude of the Public Health Problem Iron Deficiency and Reduced Work Capacity: A Critical Review of the Research to Determine a Causal Relationship 1,2 , 2001 .

[116]  C. C. Morris Pediatric Iron Poisonings in the United States , 2000, Southern medical journal.

[117]  J. Brandt,et al.  Randomised study of cognitive effects of iron supplementation in non-anaemic iron-deficient adolescent girls , 1996, The Lancet.

[118]  R. Fischer,et al.  Anemia vs iron deficiency: increased risk of preterm delivery in a prospective study. , 1992, The American journal of clinical nutrition.

[119]  S. Harder,et al.  Behandlung der akuten und chronischen Herzinsuffizienz , 1991 .

[120]  C. Colomer,et al.  Anaemia during pregnancy as a risk factor for infant iron deficiency: report from the Valencia Infant Anaemia Cohort (VIAC) study. , 1990, Paediatric and perinatal epidemiology.

[121]  Drs Du Buisson,et al.  Iron deficiency anaemia. , 1973, Nursing times.