Updates on Iron Deficiency: Gastroenterology article 1

Iron deficiency and iron deficiency anaemia: Potentially overlooked in inflammatory bowel disease

Anaemia has been acknowledged as a frequent systemic complication and/or extraintestinal manifestation in inflammatory bowel disease (IBD)¹ with iron deficiency (ID) being the primary cause of disease² with an estimated prevalence of iron deficiency anaemia (IDA) among patients with IBD at approximately 45 %.³ 

Considering the potential effect on hospitalization rates and consequences for patients quality of life, anaemia has been described as a significant and costly complication of IBD.⁴ However, ID and IDA are under-treated.⁵

Detecting and monitoring iron deficiency and iron deficiency anaemia in IBD

The pathogenesis of ID in IBD is complex, comprising intestinal bleeding, malabsorption, and inadequate oral intake.³ As symptoms of IDA mimic the symptoms of the disease such as fatigue,⁶ regular screening and diagnosis in these patients are crucial to uncover ID and IDA and therapy of anemia may even improve the quality of life better than the therapy of disease activity.⁵ 

The currently used WHO definition of anaemia⁷ also applies to patients with IBD.⁸ All patients with IBD should be assessed for the presence of anaemia through laboratory testing of blood count, serum ferritin, and C-reactive protein every 6-12 months.⁸ 

If the hemoglobin (Hb) is below normal, anaemia workup should be initiated including red blood cell distribution width (RDW) and mean corpuscular volume (MCV), reticulocyte count, differential blood cell count, serum ferritin, transferrin saturation (TSAT), and CRP concentration.⁸

Why are iron deficiency and iron deficiency anaemia overlooked in IBD?

Even when IBD patients are screened, ID and IDA might be overlooked as commonly used laboratory tests may be compromised due to several pathophysiological mechanisms related to the inflammatory nature of IBD⁹ 

Consequently, when evaluating ID and IDA in IBD the following mechanisms should be taken into consideration: 

Hemoglobin: Iron deficiency should not be excluded despite normal Hb as Hb levels do not decline until a significant amount of iron is lost.¹⁰ 

• Iron deficiency without anaemia is possible in cases with normal Hb levels in the lower limit of normality, a low MHC, or an increase in RDW.¹⁰ 

Ferritin: Besides binding and storing iron in the liver, spleen, and reticuloendothelial system ferritin is also an acute-phase protein and can be increased in the presence of inflammation.¹¹ Following, the interpretation of serum ferritin in patients with inflammation is tricky.⁵ 

• In patients without clinical, endoscopic, or biochemical evidence of active disease, serum ferritin <30 μg/L is indicative of IDA. With concomitant inflammation, such as elevated serum C reactive protein, ferritin up to 100 ug/L may still be consistent with iron deficiency⁸ 

Hepcidin and ferroportin: The hepatic peptide hormone hepcidin functions as an important regulator of iron homeostasis by controlling ferroportin – the sole iron exporter. However, hepcidin also increases as a response to inflammation.¹³ The increased levels of hepcidin caused by inflammation will promote the degradation of ferroportin and subsequently impair the exportation of cellular iron into plasma.¹³ 

• Despite normal or high levels of serum ferritin, hepcidin might compromise iron uptake as it inhibits the iron flow from the cell to the bloodstream.¹³ 

Transferrin saturation: The main iron carrier protein is transferrin.⁶ In the presence of inflammation, a normal ferritin level does not exclude ID.¹⁴ In this case, testing TSAT provides an indication of the extent of iron utilization.¹⁰ 

• Absolute ID can be defined as a combination of ferritin <100 μg/L and a TSAT <20% whereas functional ID is defined as a ferritin level >100 μg/L and a TSAT <20%.¹⁰ 

Soluble transferrin saturation receptor: The TSAT level only indicates the extent of iron utilization.⁴ A more extensive workup should include soluble transferrin receptor (sTfR) testing.⁸ sTfR is a truncated form of the cellular transferrin receptor and circulates bound to transferrin.¹⁰ It is released in proportion to the expansion of erythropoiesis in the bone marrow and is not regulated by inflammation.⁵ As a reflector of erythropoiesis, sTfR correlates with the amount of iron available. 

• Increased sTfR is consistent with all cases of functional iron deficiency, its extent being entirely independent of chronic inflammation or hepatic damage⁴ – Hence, it is a reliable indicator of iron deficiency.¹⁵

Scope of treatment

Iron supplementation is recommended by The European Chron’s and Colitis Organisation (ECCO) in all IBD patients with IDA with the goal of normalizing hemoglobin levels and iron stores.⁸ 

While oral iron substitution is safe, affordable, and easy to administer it might not be the perfect solution for patients with IBD:³ 

• According to the ECCO Guidelines Hb should be increased by > 2/dL within 4 weeks.^8,16
• As previously described patients with IBD may experience an inflammation-driven increased hepcidin blockade of the peroral absorption of iron.¹³
• Gastrointestinal side effects related to oral substitution are well known. For patients with IBD this may increase inflammation and contribute to flares.⁴ Further treatment discontinuation due to adverse events was lower in patients treated with IV iron compared to patients treated with oral iron.¹⁴
• Findings extracted from eight clinical studies exploring IV iron therapy for IDA in IBD showed that patients treated with IV iron had higher response rates compared to patients treated with oral iron.¹⁴ 

Hence, IV iron therapy is considered first-line treatment for patients with active disease, severe anemia, oral iron intolerance, and erythropoietin requirements.^3,8 

References

1. Guagnozzi D, Lucendo AJ. Anemia in inflammatory bowel disease: A neglected issue with relevant effects. World J Gastroenterol. 2014 Apr;7;20(13):3542–51.
2. Kulnigg S, Gasche C. Systematic review: managing anaemia in Crohn’s disease. Aliment Pharmacol Ther. 2006 Dec;24(11-12):1507–23.
3. Maas LA, Krishna M, Parian AM. Ironing It All Out: A Comprehensive Review of Iron Deficiency Anemia in Inflammatory Bowel Disease Patients. Dig Dis Sci. 2023 Feb;68(2):357–69.
4. Stein J, Dignass AU. Management of iron deficiency anemia in inflammatory bowel disease - a practical approach. Ann Gastroenterol. 2013;26(2):104–113.
5. Rogler G, Vavricka S. Anemia in inflammatory bowel disease: an under-estimated problem? Front Med (Lausanne). 2014;1:58.
6. Kumar A, Sharma E, Marley A, et al. Iron deficiency anaemia: pathophysiology, assessment, practical management. BMJ Open Gastroenterol. 2022 Jan;9(1):e000759.
7. World Health Organization. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity [Internet]. World Health Organization; 2011. Available from: https://apps.who.int/iris/handle/10665/85839
8. Dignass AU, Gasche C, Bettenworth D, et al. European consensus on the diagnosis and management of iron deficiency and anaemia in inflammatory bowel diseases. J Crohns Colitis. 2015 Mar;9(3):211–22.
9. Oustamanolakis P, Koutroubakis IE, Messaritakis I, et al. Soluble transferrin receptor-ferritin index in the evaluation of anemia in inflammatory bowel disease: a case-control study. Ann Gastroenterol. 2011;24(2):108–14.
10. Muñoz M, García-Erce JA, Remacha ÁF. Disorders of iron metabolism. Part II: iron deficiency and iron overload. J Clin Pathol. 2011 Apr;64(4):287–96.
11. Resál T, Farkas K, Molnár T. Iron Deficiency Anemia in Inflammatory Bowel Disease: What Do We Know? Front Med (Lausanne). 2021 Jul 1;8:686778.
12. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004 Dec 17;306(5704):2090–3.
13. Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta. 2012 Sep;1823(9):1434–43.
14. Reinisch W, Staun M, Bhandari S, et al. State of the iron: how to diagnose and efficiently treat iron deficiency anemia in inflammatory bowel disease. J Crohns Colitis. 2013 Jul;7(6):429–40.
15. Metzgeroth G, Kripp M, Müller N, et al. The soluble transferrin receptor (TfR)-F-Index is not applicable as a test for iron status in patients with chronic lymphocytic leukemia. Clin Chem Lab Med. 2009;47(10):1291–5.
16. Gasche C, Waldhoer T, Feichtenschlager T, et al. Prediction of response to iron sucrose in inflammatory bowel disease-associated anemia. Am J Gastroenterol. 2001 Aug;96(8):2382–7.
17. Howaldt S, Domènech E, Martinez N, et al. Long-Term Effectiveness of Oral Ferric Maltol vs Intravenous Ferric Carboxymaltose for the Treatment of Iron-Deficiency Anemia in Patients With Inflammatory Bowel Disease: A Randomized Controlled Noninferiority Trial. Inflamm Bowel Dis. 2022 Mar 2;28(3):373–384.
18. Gisbert JP, Bermejo F, Pajares R, et al. Oral and intravenous iron treatment in inflammatory bowel disease: hematological response and quality of life improvement. Inflamm Bowel Dis. 2009 Oct;15(10):1485–91.

Monofer®, järn(III)derisomaltos, Rx, F (subventioneras inte för patienter i hemodialys)

ATC: B03AC. Trevärt järn, parenteralt preparat. Injektions-/infusionsvätska 100 mg/ml. Injektionsflaska i förpackningsstorlekar: 1x5 ml, 1x10 ml, 5x1 ml, 5x5 ml och 2x10 ml.

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Indikation: Monofer är indicerat för behandling av järnbrist vid följande tillstånd: När perorala järnpreparat är ineffektiva eller inte kan användas. Vid kliniskt behov av snabb tillförsel av järn. Diagnosen järnbrist måste baseras på tillämpliga laboratorieprover. Kontraindikationer: Anemi som inte orsakas av järnbrist. Järnöverbelastning eller rubbning i kroppens användning av järn. Överkänslighet mot den aktiva substansen Monofer eller mot något hjälpämne. Konstaterad allvarlig överkänslighet mot andra parenterala järnprodukter. Dekompenserad leversjukdom. Särskilda varningar och försiktighetsmått: Parenteralt administrerade järnpreparat kan ge upphov till överkänslighetsreaktioner inklusive allvarliga och potentiellt dödliga anafylaktiska/anafylaktoida reaktioner. Överkänslighetsreaktioner har även rapporterats när tidigare doser av parenterala järnkomplex inte har resulterat i några oönskade effekter. Det har förekommit rapporter om överkänslighetsreaktioner som har utvecklats till Kounis syndrom. Risken är större för patienter med konstaterade allergier inklusive läkemedelsallergier, däribland patienter med svår astma, eksem eller andra atopiska allergier i anamnesen. Det finns även en ökad risk för överkänslighetsreaktioner mot parenterala järnkomplex hos patienter med immunologiska eller inflammatoriska tillstånd. Monofer ska endast administreras när personal som är utbildad i att bedöma och hantera anafylaktiska reaktioner finns tillhands, i en miljö där lokaler och utrustning för återupplivning garanterat finns tillgängliga. Varje patient ska observeras avseende biverkningar under minst 30 minuter efter varje injektion av Monofer. Om överkänslighetsreaktioner eller tecken på intolerans uppkommer under administrering måste behandlingen stoppas omedelbart. Lokaler för hjärt-lungräddning och utrustning för hantering av akuta anafylaktiska/anafylaktoida reaktioner ska finnas tillgängliga, inklusive en injicerbar 1:1 000 adrenalinlösning. Ytterligare behandling med antihistaminer och/eller kortikosteroider ges efter behov. Hos patienter med kompenserad leverdysfunktion ska parenteralt järn endast administreras efter noggrann nytta/riskbedömning. Administrering av parenteralt järn ska undvikas hos patienter med leverdysfunktion där järnöverskott är en förvärrande faktor, särskilt vid porfyria cutanea tarda (PCT). Noggrann övervakning av järnstatus rekommenderas för att undvika järnöverskott.  Parenteralt järn bör användas med försiktighet vid fall av akut eller kronisk infektion. Monofer bör inte användas för patienter med pågående bakteriemi. Hypotensiva reaktioner kan uppträda om den intravenösa injektionen ges för snabbt. Försiktighet bör vidtas för att undvika paravenöst läckage vid administrering av Monofer. Paravenöst läckage av Monofer kan leda till hudirritation och eventuellt långvarig brun missfärgning vid injektionsstället. Vid paravenöst läckage måste administreringen av Monofer stoppas omedelbart. Graviditet: Det finns endast begränsade data från användning av Monofer hos gravida kvinnor. En noggrann nytta/risk-bedömning krävs därför före användning under graviditet. Fosterbradykardi kan förekomma efter administrering av parenteralt järn. Tillståndet är vanligtvis övergående och är en följd av en överkänslighetsreaktion hos modern. Amning: Vid terapeutiska doser av Monofer förväntas inga effekter hos det ammade barnet. Produktresumé uppdaterad 2022-08-11

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