Perioperative iron deficiency anaemia

Abstract

Learning objectivesBy reading this article, you should be able to:•Describe iron physiology in health and in disease states relevant to perioperative medicine.•Interpret laboratory tests, in particular markers of iron status, in the diagnostic work-up of perioperative anaemia.•Outline the prevalence of iron deficiency anaemia in various groups of surgical patients.•Discuss the benefits and risks of treatments for perioperative anaemia including iron therapy, erythropoiesis-stimulating agents and blood transfusion.•Explain recent guidelines and clinical trials on the management of perioperative anaemia.Key points•Iron deficiency is the most common cause of anaemia, affecting at least 1.2 billion people worldwide.•Iron is essential for haemoglobin synthesis, cell growth and differentiation, oxygen sensing, muscle energetics and cellular immunity.•Systemic iron homeostasis is finely regulated by hepcidin.•Pre- and postoperative anaemia affects nearly all groups of patients and is an independent risk factor for poor clinical outcomes after both elective and non-elective surgery.•Perioperative iron deficiency anaemia is commonly treated with oral or i.v. iron with some evidence of improved clinical outcomes. Ongoing research will provide further evidence on the use of erythropoiesis-stimulating agents. By reading this article, you should be able to:•Describe iron physiology in health and in disease states relevant to perioperative medicine.•Interpret laboratory tests, in particular markers of iron status, in the diagnostic work-up of perioperative anaemia.•Outline the prevalence of iron deficiency anaemia in various groups of surgical patients.•Discuss the benefits and risks of treatments for perioperative anaemia including iron therapy, erythropoiesis-stimulating agents and blood transfusion.•Explain recent guidelines and clinical trials on the management of perioperative anaemia. •Iron deficiency is the most common cause of anaemia, affecting at least 1.2 billion people worldwide.•Iron is essential for haemoglobin synthesis, cell growth and differentiation, oxygen sensing, muscle energetics and cellular immunity.•Systemic iron homeostasis is finely regulated by hepcidin.•Pre- and postoperative anaemia affects nearly all groups of patients and is an independent risk factor for poor clinical outcomes after both elective and non-elective surgery.•Perioperative iron deficiency anaemia is commonly treated with oral or i.v. iron with some evidence of improved clinical outcomes. Ongoing research will provide further evidence on the use of erythropoiesis-stimulating agents. Iron deficiency affects ∼2 billion people worldwide.1Camaschella C. Nai A. Silvestri L. Iron metabolism and iron disorders revisited in the hepcidin era.Haematologica. 2020; 105: 260-272Crossref PubMed Scopus (257) Google Scholar It is the commonest cause of anaemia and becomes more important when we consider functional iron deficiency or iron sequestration secondary to inflammation. This review provides an update on the epidemiology, underlying mechanisms, clinical implications and management of perioperative iron deficiency anaemia in patients undergoing elective and emergency surgery. The detection and management of perioperative anaemia is one of the three key pillars of patient blood management, along with minimising blood loss and bleeding, and optimising the patient's physiological reserve of anaemia. The latter two are beyond the scope of this article and are detailed elsewhere.2Thakrar S.V. Clevenger B. Mallett S. Patient blood management and perioperative anaemia.BJA Educ. 2016; 17: 28-34Abstract Full Text Full Text PDF Scopus (23) Google Scholar The aetiology of perioperative iron deficiency anaemia is multifactorial and can be secondary to: (i) pre-existing nutritional deficiency, underlying comorbidities (e.g. cancer), or both; (ii) anaemia of inflammation; and (iii) blood loss from the surgical procedure itself. Many of these factors coexist in clinical practice. Other causes can be summarised as being attributable to:•Reduced absorption—bariatric surgery, coeliac disease, gastritis, drugs (e.g. proton pump inhibitors)•Reduced intake—eating disorders, vegetarians/vegans•Increased requirements—infants, adolescents, athletes, pregnancy, blood donors•Chronic blood loss—gastrointestinal tumours, hookworm infestation, abnormal uterine bleeding.1Camaschella C. Nai A. Silvestri L. Iron metabolism and iron disorders revisited in the hepcidin era.Haematologica. 2020; 105: 260-272Crossref PubMed Scopus (257) Google Scholar,3McNally S.A. Perioperative management of patients with anaemia: a new guideline.Br J Hosp Med (Lond). 2023; 84: 1-4Crossref Scopus (0) Google Scholar Iron is essential for haemoglobin (Hb) synthesis. Humans normally synthesise at least 2 million erythrocytes per second. Each mature red blood cell (RBC) contains 280 million molecules of Hb and each of the four globin subunits contains one iron atom in haem, resulting in the total iron flux required to maintain erythropoiesis being 2–3 × 1015 atoms per second in the adult human.4Drakesmith H. Nemeth E. Ganz T. Ironing out ferroportin.Cell Metab. 2015; 22: 777-787Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar Total body iron content is ∼3–4 g, of which 1–2 mg is lost every day, and a further 1 mg is approximately lost monthly during menstruation. Humans are unable to excrete iron actively and have therefore developed finely tuned regulatory mechanisms to control the amount of dietary iron intake, cellular iron uptake, bodily distribution and export.5Ganz T. Systemic iron homeostasis.Physiol Rev. 2013; 93: 1721-1741Crossref PubMed Scopus (720) Google Scholar Dietary iron must pass through absorptive enterocytes to enter the circulation. Haem iron is the most effectively absorbed. Inorganic non-haem ferric iron must be reduced to the soluble ferrous (Fe2+) iron by brush border ferrireductase before it can be absorbed. Systemic iron homeostasis (Fig. 1) is finely regulated by hepcidin, which is predominantly produced in the liver.5Ganz T. Systemic iron homeostasis.Physiol Rev. 2013; 93: 1721-1741Crossref PubMed Scopus (720) Google Scholar Hepcidin expression results in degradation of ferroportin, the only known mammalian exporter of iron, which blocks the release of iron from macrophages and duodenal enterocytes and subsequently reduces iron availability.5Ganz T. Systemic iron homeostasis.Physiol Rev. 2013; 93: 1721-1741Crossref PubMed Scopus (720) Google Scholar Hepcidin is upregulated in the presence of inflammation and high circulating concentrations of transferrin-bound iron, labile iron, or both. Conversely, hepcidin concentrations are decreased in iron deficiency, hypoxia, during blood loss and increased erythropoietic activity (via erythroferrone).5Ganz T. Systemic iron homeostasis.Physiol Rev. 2013; 93: 1721-1741Crossref PubMed Scopus (720) Google Scholar Genetic loss of hepcidin control leads to disorders of iron overload such as haemochromatosis, thalassaemia syndromes (α and β) and congenital dyserythropoietic anaemia.1Camaschella C. Nai A. Silvestri L. Iron metabolism and iron disorders revisited in the hepcidin era.Haematologica. 2020; 105: 260-272Crossref PubMed Scopus (257) Google Scholar Stressors such as an acute illness, infection or a surgical stress response trigger a host immune and inflammatory response resulting in profound changes in iron trafficking. The proinflammatory cytokine, interleukin (IL)-6, seems to play the most important role in developing anaemia.6Weiss G. Ganz T. Goodnough L.T. Anemia of inflammation.Blood. 2019; 133: 40-50Crossref PubMed Scopus (442) Google Scholar IL-6 upregulates hepcidin, which in turn blocks duodenal iron absorption and causes iron retention in macrophages (‘hepcidin block’) leading to a state of iron-restricted erythropoiesis. This can also be considered to be part of the evolutionary response (‘nutritional immunity’) to limit free (or non-transferrin-bound iron) for invading pathogens, particularly iron-dependent extracellular bacteria (e.g. Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia) that could otherwise cause overwhelming infection.7Drakesmith H. Prentice A.M. Hepcidin and the iron-infection axis.Science. 2012; 338: 768-772Crossref PubMed Scopus (502) Google Scholar The cytokines IL-1, IL-6, IL-10 and tumour necrosis factor (TNF)-α also promote iron sequestration into macrophages via transferrin receptor-mediated endocytosis. Inflammation also reduces production of erythropoietin and its efficacy through IL-1 and IL-6.6Weiss G. Ganz T. Goodnough L.T. Anemia of inflammation.Blood. 2019; 133: 40-50Crossref PubMed Scopus (442) Google Scholar Recovery from inflammation has been shown to lower hepcidin and IL-6 levels, leading to increased release of iron for Hb synthesis. Iron is essential for many other physiological processes such as cell growth and differentiation, neurotransmission, host defence and cardiopulmonary function.7Drakesmith H. Prentice A.M. Hepcidin and the iron-infection axis.Science. 2012; 338: 768-772Crossref PubMed Scopus (502) Google Scholar, 8Litton E. Lim J. Iron metabolism: an emerging therapeutic target in critical illness.Crit Care. 2019; 23: 81Crossref PubMed Scopus (28) Google Scholar, 9Frost J.N. Tan T.K. Abbas M. et al.Hepcidin-mediated hypoferremia disrupts immune responses to vaccination and infection.Med. 2021; 2: 164-179.e12Abstract Full Text Full Text PDF Google Scholar Many cellular proteins require iron to function. Examples include components of the mitochondrial electron transport chain. Enzymes involved in DNA metabolism, such as ribonucleotide reductase, DNA primase and DNA helicase bind iron.5Ganz T. Systemic iron homeostasis.Physiol Rev. 2013; 93: 1721-1741Crossref PubMed Scopus (720) Google Scholar The ATPase ABCE1, which is needed for messenger RNA translation, also binds iron. Iron also plays a critical role in oxygen sensing as part of the hypoxia inducible factor (HIF) pathway. The degradation of HIFs, especially HIF-2α by prolyl hydroxylases, is dependent on both iron and oxygen, and studies in healthy volunteers have demonstrated that iron depletion augments the pulmonary hypertensive response to hypoxia, whilst iron loading attenuates this response.10Frise M.C. Robbins P.A. Iron, oxygen, and the pulmonary circulation.J Appl Physiol (1985). 2015; 119: 1421-1431Crossref PubMed Scopus (0) Google Scholar Iron is also essential for immunity. Both iron deficiency and iron overload are associated with increased risk of infection.11Swenson E.R. Porcher R. Piagnerelli M. Iron deficiency and infection: another pathway to in Scopus Google Scholar has demonstrated that the immune response and to infection and J.N. Tan T.K. Abbas M. et al.Hepcidin-mediated hypoferremia disrupts immune responses to vaccination and infection.Med. 2021; 2: 164-179.e12Abstract Full Text Full Text PDF Google Scholar of perioperative anaemia a clinical and of a of is to use a Hb of to anaemia in both M. 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