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Cited by 152Iron Metabolism and DisordersErythropoietin and Anemia TreatmentHemoglobinopathies and Related Disorders

Iron deficiency or anemia of inflammation?: Differential diagnosis and mechanisms of anemia of inflammation

Open access
Nairz, Manfred, Theurl, Igor, Wolf, Dominik, Weiss, Günter·2016·Wiener Medizinische Wochenschrift
DOI 10.1007/s10354-016-0505-7PMC PMC5065583
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Abstract

Iron deficiency and immune activation are the two most frequent causes of anemia, both of which are based on disturbances of iron homeostasis. Iron deficiency anemia results from a reduction of the body's iron content due to blood loss, inadequate dietary iron intake, its malabsorption, or increased iron demand. Immune activation drives a diversion of iron fluxes from the erythropoietic bone marrow, where hemoglobinization takes place, to storage sites, particularly the mononuclear phagocytes system in liver and spleen. This results in iron-limited erythropoiesis and anemia. This review summarizes current diagnostic and pathophysiological concepts of iron deficiency anemia and anemia of inflammation, as well as combined conditions, and provides a brief outlook on novel therapeutic options.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes current diagnostic and pathophysiological concepts distinguishing iron deficiency anemia (IDA), anemia of inflammation (AI), and combined conditions, centered on immune-driven iron sequestration via the hepcidin–ferroportin axis. It outlines laboratory parameters and treatment options while noting that prospective trials and standardized diagnostics are still lacking.

Key findings

  • IDA is typically an isolated hyporegenerative microcytic hypochromic anemia with reduced ferritin (FT) and transferrin saturation (TSAT); serum FT below 30 ng/ml indicates iron deficiency with high diagnostic accuracy, and each 1 ng/ml of serum FT is generally assumed to correspond to 10 mg of stored iron.
  • AI results from immune activation diverting iron to the mononuclear phagocyte system; typical findings include low TSAT, high FT, low reticulocytes, high zinc protoporphyrin-IX, and low-to-normal erythropoietin. Hyperferritinemia >200 ng/ml with decreased TSAT suggests immune-driven iron sequestration, and hepcidin is suppressed in IDA, normal in IDA/AI, and elevated in AI.
  • Combined IDA/AI occurs in conditions such as inflammatory bowel disease or gastrointestinal/urogenital malignancy; 0.5 mg of iron is contained in the hemoglobin of 1 ml of blood, and the ferritin index (sTFR/log ferritin) can help but its cutoff depends on the diagnostic test used.
  • Treatment options include oral ferrous sulfate (approximately 100 mg elemental iron daily from 300–350-mg preparations), six available parenteral iron forms, and erythropoiesis-stimulating agents (standard starting doses 100–150 U/kg subcutaneously three times weekly). A slightly anemic target hemoglobin range of 11–12 g/dl is suggested as safe from CKD/cancer studies; TSAT <20% and FT <100 ng/ml are proposed cutoffs for absolute ID in non-dialysis CKD, with TSAT ≥20% and FT ≥100 ng/ml maintained during ESA therapy.

Methods

  • Narrative review of current diagnostic and pathophysiological concepts of IDA, AI, and combined conditions, with a brief outlook on novel therapeutic options.
  • No primary data, systematic search strategy, or formal quality appraisal is described; the paper synthesizes prior literature and mechanistic studies.
  • Main analysis is conceptual: it proposes a stepwise diagnostic approach using complete blood count, reticulocyte production index, erythrocyte indices, FT, TSAT, soluble transferrin receptor/ferritin index, reticulocyte hemoglobin content, hypochromic erythrocytes, zinc protoporphyrin, hepcidin, and GDF15, and reviews treatment strategies.

Limitations

  • Stated: the lack of data from prospective clinical trials prevents definitive recommendations on diagnostic algorithms and prognostic indices; standardization is lacking for promising tests such as soluble transferrin receptor.
  • Stated: no universally applicable algorithm can currently differentiate isolated AI from anemia with combined functional and absolute ID; hepcidin’s predictive power for iron therapy is limited in CKD patients; target therapeutic hemoglobin levels have not been defined in prospective trials.
  • Evident: as a narrative review, it does not describe a systematic literature search or evidence-grading process, and many pathophysiological claims rely on animal models or heterogeneous patient cohorts.

Model-written summary. Check it against the paper before relying on it.

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Registry

Crossref · 10.1007/s10354-016-0505-7

Cites

Statistics

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Claims the paper makes

0 of 141 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Iron stores, particularly ferritin-associated iron in liver and spleen, can become depleted during chronic bleeding episodes, repetitive blood donations, helminth infestations, materno-fetal transfer, or growth.

    “Due to this relatively inefficient process, iron stores, particularly ferritin-associated iron in liver and spleen, can become depleted during chronic bleeding episodes, repetitive blood donations, helminth infestations, through materno-fetal transfer, or during growth [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of Mammalian iron metabolism. Cell. 2010;142:24–38. source

      Not checked in the free run.

  • Premisereasoning

    Combined absolute and functional iron deficiency render interpretation of erythrocyte indices and parameters of iron status challenging.

    “Such combined conditions render the interpretation of erythrocyte indices and parameters of iron status challenging.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Parenteral iron substitution improves the clinical course of congestive heart failure in patients with coexisting iron deficiency.

    “Likewise, parenteral iron substitution has been found to improve the clinical course of CHF in patients with coexisting ID [22–24].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [22] Ebner N, Jankowska EA, Ponikowski P, et al. The impact of iron deficiency and anaemia on exercise capacity and outcomes in patients with chronic heart failure. Results from the Studies Investigating Co-morbidities Aggravating Heart Failure. Int J Cardiol. 2016;205:6–12. source

      Not checked in the free run.

    • cites [23] Silverberg DS. The role of erythropoiesis stimulating agents and intravenous (IV) iron in the cardio renal anemia syndrome. Heart Fail Rev. 2011;16:609–14. source

      Not checked in the free run.

    • cites [24] Anker SD, Comin CJ, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361:2436–48. source

      Not checked in the free run.

  • Premisereasoning

    Absolute iron deficiency usually develops when absorption of dietary iron in the duodenum and proximal jejunum cannot compensate for increased iron demand or blood loss.

    “Absolute ID, as defined by a decrease in the body’s iron content, usually develops when the absorption of dietary iron in the duodenum and proximal jejunum (Fig. 1a) cannot compensate for an increased iron demand or blood loss.”
    Quote in the paperNot a substantial claim
  • Premisenone given

    Acute and chronic infections, inflammatory disorders, and malignancies are the principal disease types underlying anemia of inflammation.

    “Acute and chronic infections, inflammatory disorders, and malignancies are the principal disease types underlying AI.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 36
  • Classified as probably not a substantial claim. 21

  • May combine two claims.

    Premisecitation

    Anemia of inflammation shares features with renal anemia in chronic kidney disease, anemia in chronic obstructive pulmonary disease, anemia in congestive heart failure without or with cardio-renal syndrome, and anemia of the elderly.

    “However, AI shares features with the renal anemia observed in patients with chronic kidney disease (CKD), the anemia in patients with chronic obstructive pulmonary disease (COPD), the anemia in patients with CHF without or with cardio-renal syndrome, and the anemia of the elderly [23, 27, 28].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [23] Silverberg DS. The role of erythropoiesis stimulating agents and intravenous (IV) iron in the cardio renal anemia syndrome. Heart Fail Rev. 2011;16:609–14. source

      Not checked in the free run.

    • cites [27] Ferrucci L, Semba RD, Guralnik JM, et al. Proinflammatory state, hepcidin, and anemia in older persons. Blood. 2010;115:3810–6. source

      Not checked in the free run.

    • cites [28] Boutou AK, Pitsiou GG, Stanopoulos I, Kontakiotis T, Kyriazis G, Argyropoulou P. Levels of inflammatory mediators in chronic obstructive pulmonary disease patients with anemia of chronic disease: a case-control study. QJM. 2012;105:657–63. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Iron deficiency occurs in two major forms: absolute and functional.

    “Iron deficiency (ID) can occur in two major forms: absolute and functional ID.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011–23. source

      Not checked in the free run.

    • cites [2] Theurl I, Fritsche G, Ludwiczek S, Garimorth K, Bellmann-Weiler R, Weiss G. The macrophage: a cellular factory at the interphase between iron and immunity for the control of infections. Biometals. 2005;18:359–67. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both absolute and functional iron deficiency can manifest isolated or combined and result in iron-deficient erythropoiesis and, if unrecognized or left untreated, anemia.

    “Both forms of ID can manifest either isolated or combined, and will result in iron-deficient erythropoiesis and, if unrecognized or left untreated, in anemia [1, 2].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011–23. source

      Not checked in the free run.

    • cites [2] Theurl I, Fritsche G, Ludwiczek S, Garimorth K, Bellmann-Weiler R, Weiss G. The macrophage: a cellular factory at the interphase between iron and immunity for the control of infections. Biometals. 2005;18:359–67. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Anemia of inflammation can be viewed as a spectrum of acute and chronic forms of anemia whose common pathophysiological denominator is their occurrence as a result of immune activation.

    “AI can be viewed as a spectrum of acute and chronic forms of anemia whose common pathophysiological denominator is their occurrence as a result of immune activation [25, 26].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Metzgeroth G, Hastka J. Iron deficiency anemia and anemia of chronic disorders. Internist (Berl). 2015;56:978–88. source

      Not checked in the free run.

    • cites [26] Weiss G. Iron metabolism in the anemia of chronic disease. Biochim Biophys Acta. 2009;1790:682–93. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Absolute and functional iron deficiency may coexist.

    “Absolute and functional iron deficiency may also coexist.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    The ultimate consequence of functional disturbances of iron homeostasis is anemia, often referred to as anemia of inflammation or anemia of chronic disease.

    “The ultimate consequence of these functional disturbances of iron homeostasis is anemia, which is often referred to as anemia of inflammation (AI) or anemia of chronic disease (ACD).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Typically, iron deficiency anemia is an isolated hyporegenerative microcytic hypochromic anemia, with reduced ferritin concentration and transferrin saturation.

    “Typically, IDA is an isolated hyporegenerative microcytic hypochromic anemia, with reduced FT concentration and TSAT as indicators of a depletion of iron stores and serum iron, respectively [12–15].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [12] Weiss G. Anemia of chronic disorders: new diagnostic tools and new treatment strategies. Semin Hematol. 2015;52:313–20. source

      Not checked in the free run.

    • cites [13] Goodnough LT, Nemeth E, Ganz T. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood. 2010;116:4754–61. source

      Not checked in the free run.

    • cites [14] Thomas L, Franck S, Messinger M, Linssen J, Thome M, Thomas C. Reticulocyte hemoglobin measurement – comparison of two methods in the diagnosis of iron-restricted erythropoiesis. Clin Chem Lab Med. 2005;43:1193–202. source

      Not checked in the free run.

    • cites [15] Archer NM, Brugnara C. Diagnosis of iron-deficient states. Crit Rev Clin Lab Sci. 2015;52:256–72. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Part of the suppression of hepcidin by erythropoietic activity may be mediated via erythroferrone, a lack of which delays recovery from anemia of inflammation in a mouse model.

    “Part of this effect may be mediated via erythroferrone (ERFE), a lack of which delays the recovery from AI in a mouse model [63].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Kautz L, Jung G, Nemeth E, Ganz T. Erythroferrone contributes to recovery from anemia of inflammation. Blood. 2015;124:2569–74. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Combined forms of iron deficiency anemia and anemia of inflammation may be present, typically in inflammatory bowel disease or gastrointestinal or urogenital malignancy.

    “In addition, combined forms of IDA and AI may be present. This scenario is typically observed in inflammatory bowel disease (IBD) or gastrointestinal or urogenital malignancy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Transferrin is a major product of hepatocytes and one of a limited number of negative acute phase reactants.

    “TF is a major product of hepatocytes and one of a limited number of negative acute phase reactants.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Hepcidin's specific receptor is ferroportin-1, whose only known function is to act as an export protein for ionic iron.

    “HAMP’s specific receptor is FPN1, whose only known function is to act as an export protein for ionic iron.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The underlying disease provides an inflammatory stimulus for sequestration of iron in the mononuclear phagocyte system.

    “At the same time, the underlying disease provides an inflammatory stimulus for the sequestration of iron in the MPS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Interleukin-10 increases transferrin receptor-1 and ferritin transcription, which may aggravate anemia of inflammation in patients with inflammatory bowel disease.

    “In parallel, interleukin (IL)-10 increases TFR1 and FT transcription, which may aggravate AI in patients with IBD [36].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Tilg H, Ulmer H, Kaser A, Weiss G. Role of IL-10 for induction of anemia during inflammation. J Immunol. 2002;169:2204–9. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    Mucosal erosions and ulcerations are associated with recurrent bleeding episodes and lead to substantial loss of iron, since 0.5 mg of iron are contained within the hemoglobin of 1 ml of blood.

    “Mucosal erosions and ulcerations are associated with recurrent bleeding episodes and lead to a substantial loss of iron, since 0.5 mg of iron are contained within the Hb of 1 ml of blood.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Transferrin receptor-1 is also expressed by neoplastic cells in solid tumors and hematologic malignancies, including chronic lymphocytic leukemia, suggesting that inflammation associated with malignant diseases may also limit iron availability for cancer cells.

    “TFR1 is also expressed by neoplastic cells in solid tumors and hematologic malignancies, including chronic lymphocytic leukemia, suggesting that inflammation associated with malignant diseases may also limit iron availability for cancer cells [49, 50].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [49] Chen G, Fillebeen C, Wang J, Pantopoulos K. Overexpression of iron regulatory protein 1 suppresses growth of tumor xenografts. Carcinogenesis. 2007;28:785–91. source

      Not checked in the free run.

    • cites [50] Smilevska T, Stamatopoulos K, Samara M, et al. Transferrin receptor-1 and 2 expression in chronic lymphocytic leukemia. Leuk Res. 2006;30:183–9. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several pathogens are able to acquire transferrin-bound iron.

    “In addition, several pathogens are able to acquire TF-bound iron [51–54].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [51] Andrews SC, Robinson AK, Rodriguez-Quinones F. Bacterial iron homeostasis. FEMS Microbiol Rev. 2003;27:215–37. source

      Not checked in the free run.

    • cites [52] Bachman MA, Lenio S, Schmidt L, Oyler JE, Weiser JN. Interaction of lipocalin 2, transferrin, and siderophores determines the replicative niche of Klebsiella pneumoniae during pneumonia. MBio. 2012;3:00224–00211. source

      Not checked in the free run.

    • cites [53] Barber MF, Elde NC. Nutritional immunity. Escape from bacterial iron piracy through rapid evolution of transferrin. Science. 2014;346:1362–6. source

      Not checked in the free run.

    • cites [54] Soares MP, Weiss G. The Iron age of host-microbe interactions. EMBO Rep. 2015;16:1482–500. source

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  • May combine two claims.

    Premisecitation

    Lipopolysaccharide enhances hepcidin production while stimulating DMT1 expression in myeloid cells, thereby favoring iron sequestration.

    “For instance, lipopolysaccharide as a component of the Gram-negative cell wall enhances HAMP production while stimulating DMT1 expression in myeloid cells, thereby favoring iron sequestration [35].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Ludwiczek S, Aigner E, Theurl I, Weiss G. Cytokine-mediated regulation of iron transport in human monocytic cells. Blood. 2003;101:4148–54. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Interleukin-6 blockade for treatment of rheumatoid arthritis lowers both disease activity and circulating hepcidin levels.

    “IL-6 is essential for the up-regulation of HAMP upon inflammation and IL-6 blockade for the treatment of rheumatoid arthritis lowers both disease activity and circulating HAMP levels [46, 47].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Lou DQ, Lesbordes JC, Nicolas G, et al. Iron- and inflammation-induced hepcidin gene expression in mice is not mediated by Kupffer cells in vivo. Hepatology. 2005;41:1056–64. source

      Not checked in the free run.

    • cites [47] Song SN, Iwahashi M, Tomosugi N, et al. Comparative evaluation of the effects of treatment with tocilizumab and TNF-alpha inhibitors on serum hepcidin, anemia response and disease activity in rheumatoid arthritis patients. Arthritis Res Ther. 2013;15:R141. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of Toll-like receptor-4, as well as pro- and anti-inflammatory cytokines, regulate hepcidin expression, while similar pathways control transcriptional expression of transferrin receptor-1, DMT1, ferroportin-1, and ferritin.

    “Activation of pattern recognition receptors such as Toll-like receptor (TLR)-4, as well as pro- and anti-inflammatory cytokines regulate HAMP expression, while similar pathways control transcriptional expression of iron transporters transferrin receptor (TFR)-1, DMT1, and FPN1, as well as the iron storage protein FT [26].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Weiss G. Iron metabolism in the anemia of chronic disease. Biochim Biophys Acta. 2009;1790:682–93. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Hepatocytes are the key source of hepcidin, while Kupffer cells are a major site of inflammation-driven iron storage.

    “Hepatocytes are the key source of HAMP, while Kupffer cells (KC) are a major site of inflammation-driven iron storage.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Menstruation, hemodialysis, requirement for repetitive blood sampling, and anticoagulant or antiplatelet drugs may contribute to iron loss in chronic kidney disease and other chronic diseases.

    “Moreover, menstruation, hemodialysis, the requirement for repetitive blood sampling, and anticoagulant or antiplatelet drugs may contribute to iron loss in CKD and other chronic diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Kupffer cells dampen hepcidin production in homeostatic conditions but may be required for inflammation-driven hepcidin secretion.

    “Interestingly, KC dampen HAMP production in homeostatic conditions but may be required for inflammation-driven HAMP secretion [44, 45].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Theurl M, Theurl I, Hochegger K, et al. Kupffer cells modulate iron homeostasis in mice via regulation of hepcidin expression. J Mol Med. 2008;86:825–35. source

      Not checked in the free run.

    • cites [45] Montosi G, Corradini E, Garuti C, et al. Kupffer cells and macrophages are not required for hepatic hepcidin activation during iron overload. Hepatology. 2005;41:545–52. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Malaria induces hepcidin, suggesting that iron sequestration is a major contributing factor to malarial anemia.

    “In addition, malaria induces HAMP, suggesting that iron sequestration is a major contributing factor to malarial anemia [100, 101].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [100] Prentice AM, Doherty CP, Abrams SA, et al. Hepcidin is the major predictor of erythrocyte iron incorporation in anemic African children. Blood. 2012;119:1922–8. source

      Not checked in the free run.

    • cites [101] Portugal S, Carret C, Recker M, et al. Host-mediated regulation of superinfection in malaria. Nat Med. 2011;17:732–7. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These pathways ultimately culminate in an insufficient renal erythropoietin response and hematopoietic erythropoietin resistance further aggravating anemia in anemia of inflammation.

    “These pathways ultimately culminate in an insufficient renal EPO response and hematopoietic EPO resistance further aggravating anemia in AI [95].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Gunnell J, Yeun JY, Depner TA, Kaysen GA. Acute-phase response predicts erythropoietin resistance in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis. 1999;33:63–72. source

      Not checked in the free run.

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    Premisecitation

    Bone morphogenetic protein-6 is primarily produced by non-parenchymal liver cells and may act in a paracrine manner on adjacent hepatocytes.

    “Notably, BMP6 is primarily produced by non-parenchymal liver cells and may act in a paracrine manner on adjacent hepatocytes [68].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Enns CA, Ahmed R, Wang J, et al. Increased iron loading induces Bmp6 expression in the non-parenchymal cells of the liver independent of the BMP-signaling pathway. PLoS ONE. 2013;8:e60534. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Serum transferrin is increased in iron deficiency, resulting in a transferrin saturation below 16%, and similar levels are observed in anemia of inflammation because transferrin is a negative acute-phase reactant.

    “In an attempt to transport the available iron as efficiently as possible, serum TF is increased in ID, resulting in a TSAT < 16 %. Similar levels are observed in AI because TF is a negative acute-phase reactant (see above).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    A reduction in serum ferritin below 30 ng/ml shows iron deficiency with high diagnostic accuracy because a strong correlation exists between serum ferritin and the body's total iron storage.

    “A reduction in serum FT below 30 ng/ml shows ID with high diagnostic accuracy because a strong correlation exists between serum FT and the body’s total iron storage.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: For each 1 ng/ml of serum ferritin, 10 mg of iron are stored in tissues and organs.

  • May combine two claims.

    Premisecitation

    In the context of inflammation, interleukin-6 and interleukin-22 stimulate hepcidin expression via specific receptors signaling through STAT-3, while alpha-1 antitrypsin may do so via hemojuvelin and matriptase-2.

    “In the context of inflammation, IL-6 and IL-22 stimulate HAMP expression via specific receptors signaling through signal transducer and activator of transcription (STAT)-3, while alpha-1 antitrypsin may do so via HJV and matriptase-2 [69–71].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [69] Armitage AE, Eddowes LA, Gileadi U, et al. Hepcidin regulation by innate immune and infectious stimuli. Blood. 2011;118:4129–39. source

      Not checked in the free run.

    • cites [70] Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271–6. source

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    • cites [71] Schaefer B, Haschka D, Finkenstedt A, et al. Impaired hepcidin expression in alpha-1-antitrypsin deficiency associated with iron overload and progressive liver disease. Hum Mol Genet. 2015;24:6254–63. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Soluble transferrin receptor is increased in iron deficiency, hemolytic anemias, thalassemia, and some hematologic malignancies, while its levels tend to be normal in anemia of inflammation.

    “sTFR is increased in ID, hemolytic anemias, thalassemia, and some hematologic malignancies, while its levels tend to be normal in AI [112].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Theurl I, Aigner E, Theurl M, et al. Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood. 2009;113:5277–86. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Iron deficiency anemia is a microcytic hypochromic anemia, while anemia of inflammation may be microcytic hypochromic or normocytic normochromic in appearance.

    “IDA is a microcytic hypochromic anemia, while AI may be microcytic hypochromic or normocytic normochromic in appearance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    An increase in the ratio of zinc protoporphyrin to heme indicates iron deficiency for erythropoiesis and is observed in iron deficiency anemia, anemia of inflammation, myelodysplastic syndromes, and sideroblastic anemias, including the form secondary to lead intoxication.

    “Since ZnPP and heme are analogues, an increase in the ratio of ZnPP/heme indicates ID for erythropoiesis and is observed in IDA, AI, MDS, and sideroblastic anemias, including the form secondary to lead intoxication [117].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Archer NM, Brugnara C. Diagnosis of iron-deficient states. Crit Rev Clin Lab Sci. 2015;52:256–72. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Estradiol inhibits hepcidin transcription in hepatocytes, which may allow for higher intestinal iron absorption to compensate for average 20-80 ml of monthly menstrual blood loss.

    “Estradiol, whose levels increase after menstrual bleeding during the first half of the menstrual cycle (follicular phase) until ovulation, inhibits HAMP transcription in hepatocytes, which may allow for higher intestinal iron absorption to compensate for the average 20–80 ml of monthly menstrual blood loss [73, 74].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [73] Yang Q, Jian J, Katz S, Abramson SB, Huang X. 17beta-Estradiol inhibits iron hormone hepcidin through an estrogen responsive element half-site. Endocrinology. 2012;153:3170–8. source

      Not checked in the free run.

    • cites [74] Higham JM, O’Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol. 1990;97:734–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bone morphogenetic protein-6 binds to a heterodimeric receptor complexed with hemojuvelin and matriptase-2, and stimulates hepcidin expression.

    “BMP6 binds to a heterodimeric receptor complexed with hemojuvelin (HJV) and matriptase-2 (the gene product of TMPRSS6), and stimulates HAMP expression [66, 67].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [66] Andriopoulos B Jr., Corradini E, Xia Y, et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet. 2009;41:482–7. source

      Not checked in the free run.

    • cites [67] Babitt JL, Huang FW, Wrighting DM, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38:531–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    While hepatic hepcidin formation is increased during inflammation, erythropoietin production in the kidney is subject to inhibition by inflammatory mediators such as tumor necrosis factor and interleukin-1.

    “While hepatic HAMP formation is increased during inflammation, EPO production in the kidney is subject to inhibition by inflammatory mediators such as tumor necrosis factor (TNF) and IL-1 [82–84].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [82] Jelkmann W. Proinflammatory cytokines lowering erythropoietin production. J Interferon Cytokine Res. 1998;18:555–9. source

      Not checked in the free run.

    • cites [83] Rodriguez RM, Corwin HL, Gettinger A, Corwin MJ, Gubler D, Pearl RG. Nutritional deficiencies and blunted erythropoietin response as causes of the anemia of critical illness. J Crit Care. 2001;16:36–41. source

      Not checked in the free run.

    • cites [84] Artunc F, Risler T. Serum erythropoietin concentrations and responses to anaemia in patients with or without chronic kidney disease. Nephrol Dial Transplant. 2007;22:2900–8. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hepcidin is suppressed in iron deficiency anemia, in the normal range in combined iron deficiency anemia and anemia of inflammation, and elevated in anemia of inflammation.

    “For instance, HAMP is suppressed in IDA, in the normal range in IDA/AI, and elevated in AI [112, 118].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [112] Theurl I, Aigner E, Theurl M, et al. Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood. 2009;113:5277–86. source

      Not checked in the free run.

    • cites [118] Bergamaschi G, Di Sabatino A, Albertini R, et al. Serum hepcidin in inflammatory bowel diseases: biological and clinical significance. Inflamm Bowel Dis. 2013;19:2166–72. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elevated hepcidin levels have been reported in patients with HIV infection, in which they are associated with anemia and independently predict mortality.

    “Elevated HAMP levels have also been reported in patients with HIV (Human immunodeficiency virus) infection, in which they are associated with anemia and independently predict mortality [102].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Minchella PA, Armitage AE, Darboe B, et al. Elevated Hepcidin is part of a complex relation that links mortality with iron homeostasis and anemia in men and women with HIV infection. J Nutr. 2015;145:1194–201. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypoxia has a similar effect on hepcidin that is mediated via platelet-derived growth factor isoform BB, which may enable the required increase of hemoglobin levels at high altitude.

    “Hypoxia has a similar effect on HAMP that is mediated via platelet-derived growth factor isoform BB (PDGF-BB), which may enable the required increase of Hb levels at high altitude [65].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Sonnweber T, Nachbaur D, Schroll A, et al. Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB. Gut. 2014;63:1951–9. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In AI patients under causative treatment for their underlying condition, EPO resistance of the erythron or renal EPO deficiency may be present.

    “EPO resistance of the erythron or renal EPO deficiency may be present”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Many subjects with AI who are under causative treatment for their underlying condition do not have an adequate Hb response to iron therapy.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An FPN1 stabilizing antibody is currently under investigation.

    “Moreover, an FPN1 stabilizing antibody is currently also under investigation [159].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [159] Witcher DR, Leung D, Hill KA, et al. LY2928507, an antibody targeting ferroportin, is a potent inhibitor of hepcidin activity and increases iron mobilization in normal cynomolgus monkeys. Blood. 2013;122. https://ash.confex.com/ash/2013/webprogram/Paper58923.html source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Prolyl hydroxylase inhibitors can be orally administered.

    “This class of drugs can be orally administered”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160] Soni H. Prolyl hydroxylase domain-2 (PHD2) inhibition may be a better therapeutic strategy in renal anemia. Med Hypotheses. 2014;82:547–50. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Iron salts are absorbed by the sequential action of DMT1 and ferroportin-1 and associated oxidoreductases, but have low bioavailability.

    “These iron salts are absorbed by the sequential action of DMT1 and FPN1 and associated oxidoreductases, but have a low bioavailability.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    There is concern that iron supplementation may stimulate pathogen proliferation or result in a flare of an underlying inflammatory disorder or malignancy.

    “Therefore, there is the concern that iron supplementation may stimulate pathogen proliferation or result in a flare of an underlying inflammatory disorder or malignancy [54, 124, 125].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [54] Soares MP, Weiss G. The Iron age of host-microbe interactions. EMBO Rep. 2015;16:1482–500. source

      Not checked in the free run.

    • cites [124] Schaible UE, Kaufmann SH. A nutritive view on the host-pathogen interplay. Trends Microbiol. 2005;13:373–80. source

      Not checked in the free run.

    • cites [125] Nairz M, Haschka D, Demetz E, Weiss G. Iron at the interface of immunity and infection. Front Pharmacol. 2015;5:152.

      Not checked in the free run.

    • The authors state this as an assumption: Anemia of inflammation is the pathophysiological consequence of the body's attempt to reduce the availability of iron for infectious agents.

  • May combine two claims.

    Premisecitation

    Protection of HIF from degradation increases EPO levels and erythropoietic iron availability.

    “which increases EPO levels and erythropoietic iron availability [160]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [160] Soni H. Prolyl hydroxylase domain-2 (PHD2) inhibition may be a better therapeutic strategy in renal anemia. Med Hypotheses. 2014;82:547–50. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Official approval of ESA for MDS is still pending.

    “official approval of this approach is still pending [147]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Santini V. Anemia as the main manifestation of myelodysplastic syndromes. Semin Hematol. 2015;52:348–56. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Frequent administration of low doses of parenteral iron may be beneficial.

    “Since parenteral iron stimulates HAMP secretion, as documented in hemodialysis patients, frequent administration of low doses may be beneficial [141].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [141] Kitsati N, Liakos D, Ermeidi E, et al. Rapid elevation of transferrin saturation and serum hepcidin concentration in hemodialysis patients after intravenous iron infusion. Haematologica. 2015;100:e80–e83. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Heme products are absorbed by alternative pathways that are incompletely characterized, since the proposed solute carrier SLC46A1 absorbs folate more efficiently than heme.

    “These are absorbed by alternative pathways that are incompletely characterized, since the proposed solute carrier SLC46A1 absorbs folate more efficiently than heme [132, 133].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [132] Shayeghi M, Latunde-Dada GO, Oakhill JS, et al. Identification of an intestinal heme transporter. Cell. 2005;122:789–801. source

      Not checked in the free run.

    • cites [133] Qiu A, Jansen M, Sakaris A, et al. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell. 2006;127:917–28. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Growth-differentiation factor-15 is normal in iron deficiency anemia and elevated in anemia of inflammation and combined iron deficiency anemia and anemia of inflammation.

    “GDF15 is normal in IDA and elevated in AI and IDA/AI [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Theurl I, Finkenstedt A, Schroll A, et al. Growth differentiation factor 15 in anaemia of chronic disease, iron deficiency anaemia and mixed type anaemia. Br J Haematol. 2010;148:449–55. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Blocking HAMP expression or processing, neutralizing circulating HAMP, and blocking its interaction with FPN1 are under active investigation for the treatment of AI.

    “Blocking HAMP expression or processing, neutralization of circulating HAMP, and blockage of its interaction with FPN1 are under active investigation for the treatment of AI.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Lack of data from prospective clinical trials prevents definitive recommendations on diagnostic algorithms and prognostic indices.

    “Currently, the lack of data from prospective clinical trials prevents definitive recommendations on diagnostic algorithms and prognostic indices.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Lack of standardization in otherwise promising tests, such as measurement of sTFR, aggravates these problems.

    “These problems are aggravated by the lack of standardization in otherwise promising tests, such as measurement of sTFR.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In MDS, ESA are in wide clinical use.

    “In MDS, ESA are in wide clinical use”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Santini V. Anemia as the main manifestation of myelodysplastic syndromes. Semin Hematol. 2015;52:348–56. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Transferrin saturation below 20% and ferritin below 100 ng/ml have been proposed as cutoffs for absolute iron deficiency in non-dialysis chronic kidney disease patients.

    “TSAT < 20 % and FT < 100 ng/ml have been proposed as cutoffs for absolute ID in non-dialysis CKD patients [142].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [142] Fernandez-Rodriguez AM, Guindeo-Casasus MC, Molero-Labarta T, et al. Diagnosis of iron deficiency in chronic renal failure. Am J Kidney Dis. 1999;34:508–13. source

      Not checked in the free run.

52 of 52

  • The authors state this as an assumption.

    For each 1 ng/ml of serum ferritin, 10 mg of iron are stored in tissues and organs.

    “It is generally assumed that for each 1 ng/ml of serum FT, 10 mg of iron are stored in tissues and organs.”

  • The authors state this as an assumption.

    Anemia of inflammation is the pathophysiological consequence of the body's attempt to reduce the availability of iron for infectious agents.

    “It is generally assumed, similar to the hypoferremia of the acute phase response, that AI is the pathophysiological consequence of the body’s attempt to reduce the availability of iron for infectious agents.”

  • The paper relies on this without support.

    Many subjects with AI who are under causative treatment for their underlying condition do not have an adequate Hb response to iron therapy.

    “Many subjects with AI who are under causative treatment for their underlying condition do not have an adequate Hb response to iron therapy.”

  • The paper relies on this without support.

    HAMP has an important role for iron sequestration in AI.

    “Given its important role for iron-sequestration in AI”

  • The paper relies on this without support.

    Treatment strategies differ between IDA, AI, and a combination of both forms.

    “The precise differential diagnosis between IDA, AI, and a combination of both forms is of clinical importance because of differing treatment strategies.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Many pathophysiologic features of anemia of chronic disease suggest that this form of anemia is an intended mechanism of defense against infections that aims at withdrawing iron, oxygen or both from pathogens.

    “Many of the pathophysiologic features of ACD suggest that this form of anemia is an intended mechanism of defense against infections which aims at withdrawing iron, oxygen or both from pathogens (Gil-Marques et al., 2018;Nairz et al., 2016;Siegert et al., 2015).”

    From Iron in infection and immunity (2020) · cites this paper as Nairz et al., 2016

    The Introduction (page unavailable) describes immune activation diverting iron into storage and producing iron-restricted anemia. The Liver section (page unavailable) explicitly calls reduced serum transferrin a mechanism of microbial iron withdrawal. The cited passages do not establish that anemia itself is an intended defense or that it withdraws oxygen from pathogens. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • HB of aged RBC is recycled, daily providing an additional 20-25 mg of iron.

    “Rather, HB of aged RBC (aRBC) is recycled, daily providing additional 20-25 mg of iron (Nairz et al., 2016).”

    From Iron in infection and immunity (2020) · cites this paper as Nairz et al., 2016

The citation lists haven’t been fetched yet

References 162 · Cited by 152

Research works printed but not linked: 1

  1. Archer NM, Brugnara C. Diagnosis of iron-deficient states. Crit Rev Clin Lab Sci. 2015;52:256–72. · DOI · Paper page

Authors
Nairz, M., Theurl, I., Wolf, D., & Weiss, G.
Affiliations
  • Innsbruck Medical University (AT)
  • University Hospital Bonn (DE)
Corresponding author
  • Nairz, Manfred
  • Weiss, Günter
ORCID
Venue
Wiener Medizinische Wochenschrift
Publisher
Springer Science and Business Media LLC
Published
2016-08-24
Volume
166
Issue
13-14
Pages
411-423
ISSN
  • 0043-5341 (ISSN-L)
  • 1563-258X
DOI
10.1007/s10354-016-0505-7
PMC
PMC5065583
OpenAlex
W2515065660
Semantic Scholar
2bf5098a355a69463938f389e9f8d96bd8257075
Cited by
152
References
162
Citations by year
2026: 10 · 2025: 15 · 2024: 19 · 2023: 13 · 2022: 16 · 2021: 14 · 2020: 16 · 2019: 20 · 2018: 18 · 2017: 11
FWCI
15.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Wiener Medizinische Wochenschrift (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Austrian Science Fund (TRP 188, P 28302)
  • Medizinische Universität Innsbruck
  • Universität Innsbruck
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
  • Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
Keywords
iron deficiency anemia, anemia of chronic disease, iron homeostasis, immune activation, anemia diagnosis, anemia treatment
MeSH terms
Animals, Diagnosis, Differential, Erythropoiesis, Ferritins, Hemoglobinometry, Homeostasis, Humans, Inflammation, Iron, Macrophages, Anemia, Iron-Deficiency, Inflammation Mediators, Hepcidins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

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