Iron deficiency

doi:10.1016/S0140-6736(20)32594-0

The Lancet

Volume 397, Issue 10270, 16–22 January 2021, Pages 233-248

https://doi.org/10.1016/S0140-6736(20)32594-0 Get rights and content

Summary

Iron deficiency is one of the leading contributors to the global burden of disease, and particularly affects children, premenopausal women, and people in low-income and middle-income countries. Anaemia is one of many consequences of iron deficiency, and clinical and functional impairments can occur in the absence of anaemia. Iron deprivation from erythroblasts and other tissues occurs when total body stores of iron are low or when inflammation causes withholding of iron from the plasma, particularly through the action of hepcidin, the main regulator of systemic iron homoeostasis. Oral iron therapy is the first line of treatment in most cases. Hepcidin upregulation by oral iron supplementation limits the absorption efficiency of high-dose oral iron supplementation, and of oral iron during inflammation. Modern parenteral iron formulations have substantially altered iron treatment and enable rapid, safe total-dose iron replacement. An underlying cause should be sought in all patients presenting with iron deficiency: screening for coeliac disease should be considered routinely, and endoscopic investigation to exclude bleeding gastrointestinal lesions is warranted in men and postmenopausal women presenting with iron deficiency anaemia. Iron supplementation programmes in low-income countries comprise part of the solution to meeting WHO Global Nutrition Targets.

Introduction

Iron deficiency (ID) and iron deficiency anaemia (IDA) cause an immense disease burden worldwide. Globally, there were over 1·2 billion cases of IDA in 2016.¹ IDA is among the five greatest causes of years lived with disability globally, the leading cause of years lived with disability in low-income and middle-income countries (LMICs), and is the leading cause of years lived with disability among women across 35 countries.¹ Controlling anaemia is a global health priority: WHO is aiming for a 50% reduction in anaemia prevalence in women by 2025.²

When iron intake is inadequate to meet requirements or to compensate for physiological or pathological losses, body iron stores become depleted. Absolute ID occurs when iron stores are insufficient to meet the needs of the individual, and is particularly common in young children (younger than 5 years) and premenopausal (especially pregnant) women. In patients with inflammation, withholding of iron from the plasma promotes iron deficient erythropoiesis and anaemia despite adequate body iron stores (functional iron deficiency). This process is common in patients with complex medical or surgical disorders, in people living in areas where infection prevalence is high, and in patients receiving erythropoiesis stimulating agents.³

Iron is crucial for numerous physiological and cellular processes, and ID causes diverse health consequences. Management of ID is an important and complex challenge faced by practitioners of medicine, nutrition, and public health worldwide. In this Seminar, we update the physiology, diagnosis, and clinical management of ID and identify future translational and clinical research directions.

Section snippets

Clinical presentation

ID can cause symptoms both in the presence and absence of anaemia, or can be asymptomatic. Common symptoms and signs include fatigue and lethargy, reduced concentration, dizziness, tinnitus, pallor, and headache. In susceptible individuals, ID promotes restless leg syndrome.⁴ Other presentations include alopecia, dry hair or skin, koilonychia, and atrophic glossitis. Symptoms in infants (aged younger than 12 months) with ID can include poor feeding and irritability.⁵ Patients might also present

Epidemiology of ID

In 2016, 41·7% of children (younger than 5 years), 40·1% of pregnant women, and 32·5% of non-pregnant women were anaemic worldwide.11, 12 WHO estimates that 42% of anaemia cases in children and 50% in women are amenable to iron supplementation, with variation between regions.¹³ Meta-analyses of population studies suggest the contribution of ID to anaemia could be smaller than the WHO estimate: 25% in children and 37% in women.¹⁴ Because of the paucity of population studies measuring iron

Molecular pathology of ID

Most body iron is contained in haemoglobin found in erythrocytes (2500 mg), and much of the remaining iron is contained in myoglobin (130 mg) and enzymes (150 mg), with surplus iron stored in the liver; average iron stores the US population are 9·7 mg/kg in men, 5·7 mg/kg in premenopausal women, and 7·8 mg/kg in postmenopausal women.¹⁹ The 0·1% of total body iron contained in plasma is bound to transferrin, and in this form, iron can be supplied to tissues via binding to the transferrin

Clinical pathophysiology of absolute ID

The main causes of absolute ID are excessive blood loss, and inadequate dietary iron intake or absorption that fails to meet physiological requirements (panel 1).

Diagnosis of ID

The gold standard test for absolute ID is the finding of absent stainable bone marrow iron. Patients with functional ID have detectable stainable bone marrow iron unless they have concomitant absolute ID (figure 2). Bone marrow aspiration is invasive and rarely done routinely for diagnosis of ID, but it remains useful in complex cases. ID is usually diagnosed by blood biomarkers (figure 3). A full blood count with film can indicate anaemia, microcytic, hypochromic red blood cells with an

Further investigation of ID

ID is the presenting manifestation of various pathophysiological processes, and investigation to exclude serious pathology and define the underlying cause is essential. The nature and extent of testing depends on the patient demographic (appendix p 1).

Coeliac serological testing should be considered in patients with non-anaemic ID and is recommended for all patients with IDA.33, 91 Measurement of tissue transglutaminase IgA antibodies is the preferred test, and should be combined with IgA

Treatment of ID

A holistic approach to clinical management of ID is outlined in the appendix (p 2). The aim of treatment is to replenish iron stores and normalise haemoglobin concentrations if anaemia is present. Indications for therapy in ID include anaemia, symptoms, crucial periods that risk impaired outcomes (eg, pregnancy or before surgery), and when progression is likely to be due to uncorrected underlying factors; for example, ongoing growth in children, poor iron intake, or blood losses. Most patients

Oral iron supplementation

Many oral iron products with varying doses and formulations are available. Oral iron formulations include ferrous salts (eg, ferrous sulphate) as well as other agents, including iron polymaltose. Dosing is based on the elemental iron content (eg, 325 mg ferrous sulphate contains 105 mg elemental iron). The use of ferrous salts for iron therapy is limited by gastrointestinal adverse events. A systematic review of placebo-controlled trials supported that ferrous salts increased gastrointestinal

Parenteral iron therapy

New generation parenteral iron preparations have revolutionised therapy for ID. Intravenous preparations comprise an iron core encapsulated in a carbohydrate shell to delay iron release.¹⁰³ The maximum single infusion dose depends on the stability of the shell. Iron sucrose has a less stable shell, limiting dosing to about 200 mg per infusion.¹⁰³ Ferric carboxymaltose, ferric derisomaltose, and ferumoxytol have stable shells, slowing iron release and allowing higher doses of iron to be

Clinical benefits of iron therapy

Oral iron is the first line of treatment in uncomplicated ID, but the threshold for use of parenteral iron in cases of moderate or severe anaemia, severe clinical symptoms, poor response, intolerable adverse effects, or difficult adherence is lowering. Parenteral iron generally promotes superior haemoglobin improvements: for example, a systematic review of 13 RCTs showed parenteral iron produces a 5·3 g/L (95% CI 2·1–7·5) greater increase in haemoglobin compared with oral iron.¹²¹

Iron interventions in patients without complex medical conditions

Iron supplementation inevitably increases haemoglobin and ferritin.122, 123, 124, 125 Clinically, iron in adults with non-anaemic ID reduces self-reported fatigue (standardised mean difference [MD] −0·38 [95% CI −0·52 to −0·23]).¹²⁶ Trials of iron in asymptomatic (non-fatigued) women with ID have shown that iron does not generally improve fatigue scores, suggesting that iron benefits patients with ID who present symptomatically but not patients with ID who are asymptomatic. Iron can improve

Parenteral iron in patients with complex conditions

Impaired oral iron use in functional ID can be circumvented by parenteral iron. Parenteral iron should be considered in the first line of treatment for functional ID, including for patients with the following complex conditions.

Preventing ID in LMICs

At the population level, ID and IDA is an outcome of social, environmental, and nutritional determinants that converge to constrain iron intake, increase iron demands, cause blood loss due to helminth infection, and limit iron absorption and use due to inflammation.¹⁵⁴ WHO recommends population level interventions to prevent ID,¹⁵⁵ including central fortification with iron of staple foods and condiments; home fortification of infant complementary foods with iron and other micronutrients; and

Conclusions

Clinicians regularly encounter ID and IDA. Understanding the pathophysiology of absolute and functional ID guides diagnosis, appropriate use of established and emerging treatments, and rational deployment of further investigations. Further research into the biology, epidemiology, diagnosis, and treatment of ID (panel 2) will continue to transform approaches to this common condition.

Search strategy and selection criteria

We searched MEDLINE, Embase, and the Cochrane Register, with combinations of the search terms including (“iron” OR “iron deficiency” OR “iron deficiency an[a]emia” OR “an[a]emia” OR “supplementation” OR “ferrous”OR “ferric” OR “ferric carboxymaltose”OR “iron carboxymaltose”OR “iron isomaltoside”OR “ferric derisomaltoside”OR “ferumoxytol” OR “iron sucrose” OR “iron polymaltose”OR “iron dextran” OR “nutrition”OR “iron absorption” OR “c[o]eliac disease” OR “ferritin”OR “hepcidin”OR “ferroportin”

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Cardiac fibrosis is a major public health problem worldwide, with high morbidity and mortality, affecting almost all patients with heart disease worldwide. It is characterized by fibroblast activation, abnormal proliferation, excessive deposition, and abnormal distribution of extracellular matrix (ECM) proteins. The maladaptive process of cardiac fibrosis is complex and often involves multiple mechanisms. With the increasing research on cardiac fibrosis, redox has been recognized as an important part of cardiac remodeling, and an imbalance in redox homeostasis can adversely affect the function and structure of the heart. The metabolism of metal ions is essential for life, and abnormal metabolism of metal ions in cells can impair a variety of biochemical processes, especially redox. However, current research on metal ion metabolism is still very limited. This review comprehensively examines the effects of metal ion (iron, copper, calcium, and zinc) metabolism-mediated redox homeostasis on cardiac fibrosis, outlines possible therapeutic interventions, and addresses ongoing challenges in this rapidly evolving field.
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Iron overload occurs due to excessive iron intake compared to the body’s demand, leading to iron deposition and impairment of multiple organ functions. Our previous study demonstrated that chronic oral administration of ferric citrate (FC) caused colonic inflammatory injury. However, the precise mechanism underlying this inflammatory response remains unclear. The current study aims to investigate the mechanism by which iron overload induced by FC exposure leads to colonic inflammation. To accomplish this, mice were orally exposed to three different concentrations of FC (71 mg/kg/bw (L), 143 mg/kg/bw (M) and 286 mg/kg/bw (H)) for continuous 16 weeks, with the control group receiving ultrapure water (C). Exposure to FC caused disturbances in the excretory system, altered colonic flora alpha diversity, and enriched pathogenic bacteria, such as Mucispirillum, Helicobacter, Desulfovibrio, and Shigella. These changes led to structural disorders of the colonic flora and an inflammatory response phenotype characterized by inflammatory cells infiltration, atrophy of intestinal glands, and irregular thickening of the intestinal wall. Mechanistic studies revealed that FC-exposure activated the NF-κB signaling pathway by up-regulating TLR4, MyD88, and NF-κB mRNA levels and protein expression. This activation resulted in increased production of pro-inflammatory cytokines, further contributing to the colonic inflammation. Additionally, in vitro experiments in SW480 cells confirmed the activation of NF-κB signaling pathway by FC exposure, consistent with the in vivo findings. The significance of this study lies in its elucidation of the mechanism by which iron overload caused by FC exposure leads to colonic inflammation. By identifying the role of pathogenic bacteria and the NF-κB signaling pathway, this study could potentially offer a crucial theoretical foundation for the research on iron overload, as well as provide valuable insights for clinical iron supplementation.
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SeminarIron deficiency

Summary

Introduction

Section snippets

Clinical presentation

Epidemiology of ID

Molecular pathology of ID

Clinical pathophysiology of absolute ID

Diagnosis of ID

Further investigation of ID

Treatment of ID

Oral iron supplementation

Parenteral iron therapy

Clinical benefits of iron therapy

Iron interventions in patients without complex medical conditions

Parenteral iron in patients with complex conditions

Preventing ID in LMICs

Conclusions

Search strategy and selection criteria

Lancet

Lancet

Lancet Glob Health

Am J Clin Nutr

Am J Clin Nutr

Cell

Blood

Blood

Blood

Blood

Blood

J Biol Chem

J Pediatr Adolesc Gynecol

Am J Med

Am J Clin Nutr

Am J Clin Nutr

Gastroenterology

Gastroenterology

Lancet

Clin Gastroenterol Hepatol

Gastroenterology

Am J Clin Nutr

Am J Clin Nutr

J Nutr

J Nutr

Am J Clin Nutr

Am J Clin Nutr

Am J Clin Nutr

Clin Gastroenterol Hepatol

Blood

Gastroenterology

Blood

Lancet Haematol

Adv Chronic Kidney Dis

Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

Lancet

Global nutrition targets 2025: policy brief series

Anemia of Inflammation

N Engl J Med

Iron needs of babies and children

Paediatr Child Health

Disorders of iron metabolism

N Engl J Med

Differences in clinical profile and outcomes of low iron storage vs defective iron utilization in patients with heart failure: results from the DEFINE-HF and BIOSTAT-CHF studies

JAMA Cardiol

Deceitful red-flag: angina secondary to iron deficiency anaemia as a presenting complaint for underlying malignancy

BMJ Case Rep

Anaemia in children <5 years

Prevalence of anaemia in women

The global prevalence of anaemia in 2011

The proportion of anemia associated with iron deficiency in low, medium, and high human development index countries: a systematic analysis of national surveys

Nutrients

Anemia. 4727.0.55.003—Australian Aboriginal and Torres Strait Islander health survey: biomedical results, 2012–13

Evidence-based clinical guidelines for immigrants and refugees

CMAJ

Quantification of body iron and iron absorption in the REDS-II donor iron status evaluation (RISE) study

Transfusion

Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms

Nature

Impact of menstrual blood loss and diet on iron deficiency among women in the UK

Br J Nutr

Seminar
Iron deficiency