Iron deficiency (ID) is the most common micronutrient deficiency worldwide with >20% of women experiencing it during their reproductive lives. Hepcidin, a peptide hormone mostly produced by the liver, controls the absorption and regulation of iron. Understanding iron metabolism is pivotal in the successful management of ID and iron deficiency anaemia (IDA) using oral preparations, parenteral iron or blood transfusion.
Oral preparations vary in their iron content and can result in gastrointestinal side effects. Parenteral iron is indicated when there are compliance/tolerance issues with oral iron, comorbidities which may affect absorption or ongoing iron losses that exceed absorptive capacity. It may also be the preferred option when rapid iron repletion is required to prevent physiological decompensation or given preoperatively for non-deferrable surgery.
As gynaecologists, we focus on managing women’s heavy menstrual bleeding (HMB) and assume that primary care clinicians are treating the associated ID/IDA. We now need to take the lead in diagnosing, managing and initiating treatment for ID/IDA and treating HMB simultaneously. This dual management will significantly improve their quality of life.
In this chapter we will summarise the importance of iron in cellular functioning, describe how to diagnose ID/IDA and help clinicians choose between the available treatment options.
Highlights
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Iron deficiency (ID) is the most common micronutrient deficiency worldwide with >20% of women experiencing it during their reproductive lives.
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Oral preparations vary in their iron content and can result in gastrointestinal side effects. Parenteral iron is indicated when there are compliance/tolerance issues with oral iron, comorbidities, which may affect absorption or ongoing iron losses that exceed absorptive capacity.
- •
As gynaecologists, we focus on managing women’s heavy menstrual bleeding (HMB) and assume that primary care clinicians are treating the associated ID/IDA. We now need to take the lead in diagnosing, managing and initiating treatment for ID/IDA and treating HMB simultaneously.
- •
In this study, we will summarise the importance of iron in cellular functioning, describe how to diagnose ID/IDA and help clinicians choose between the available treatment options.
Introduction
Iron deficiency (ID) is the commonest micronutrient deficiency worldwide and is defined as a reduction of total body iron As a result, there may be impairment of oxygen transportation and enzyme reactions involved in nearly all major metabolic pathways. ID may occur with or without anaemia defined as a decreased quantity of erythrocytes or level of haemoglobin associated with morphological changes in erythrocytes . Anaemia has been wrongly considered as an indicator of ID. However, it is only with progressive iron depletion and its associated functional impairment that anaemia finally develops . Furthermore, haemoglobin concentration has a low sensitivity and specificity for ID .
Iron-restricted erythropoiesis and functional ID occur in those with chronic inflammation, cancer or renal disease. This is because inflammatory processes impair the delivery of iron to red cell precursors, irrespective of iron stores, with mobilisation of iron from stores insufficient to meet metabolic demands. This can also be observed following treatment with erythropoiesis-stimulating agents .
Incidence and prevalence of ID/IDA
Anaemia is a global health problem affecting both low- and high-income countries with social and economic consequences for all . Anaemia impairs the health and well-being of women and increases the risk of adverse maternal and neonatal outcomes . Worldwide anaemia accounted for 68.4 million years of life lived with a disability in 2010, an increase from 65.5 million years of life in 1990 . However, during this time frame, the prevalence of anaemia decreased from 40.2% to 32.9% . The difference in the incidence and prevalence of anaemia is likely to be due to increasing global population and increased survival among those with chronic, often inflammatory, diseases .
In 2011, the global prevalence of anaemia was 38% in pregnant women (32.4 million women) and 29% in all non-pregnant women (496 million women) . Therefore, a worldwide total of 528 million women of reproductive age are anaemic, of which 20 million are severely affected . There are wide variations in global prevalence reflecting economic status and associated nutritional deficiencies, but no country is exempt .
Given the magnitude of its worldwide prevalence, the World Health Organization (WHO) included a 50% reduction in anaemia for women of reproductive age as one of its six global nutritional targets for 2025 . The aim is to increase the identification and understanding of anaemia in women and increase prevention and management .
Worldwide the most common cause of anaemia is ID , accounting for approximately 50% of cases . Furthermore, the prevalence of ID is at least double that of iron deficiency anaemia (IDA), with more than 2 billion people affected . Other common causes of anaemia include haemoglobinopathy, schistosomiasis, parasites , other micronutrient deficiencies (such as vitamin B 12 , folate and riboflavin) and acute and chronic infections (HIV, cancer and tuberculosis) . These conditions often co-exist with ID 9 . Uterine fibroids and other gynaecological conditions are respectively the 13th and 26th most common causes of anaemia worldwide . The prevalence of these gynaecological conditions peaks at a young age and decreases steadily as women age . From the age of 15 until old age, anaemia more commonly affects women than men .
In a recent European survey, one in 10 of the population sampled had or have had ID or IDA at some point in their lifetime. Forty percent of Europeans sampled during the survey felt that ID had negatively affected their family life. Furthermore, time from initial symptoms to diagnosis was 2.5 years, and even with a diagnosis, 1 in 10 respondents did not receive medical management .
When treating women with heavy menstrual bleeding (HMB), we focus on the underlying causes of their blood loss and offer medical and surgical options to reduce this bleeding. We may check for anaemia, but rarely implement timely and appropriate treatment for ID. This study will consider iron metabolism and its importance in the body’s physiological processes, the aetiology and assessment of ID and IDA and our role in the management of these conditions.
Incidence and prevalence of ID/IDA
Anaemia is a global health problem affecting both low- and high-income countries with social and economic consequences for all . Anaemia impairs the health and well-being of women and increases the risk of adverse maternal and neonatal outcomes . Worldwide anaemia accounted for 68.4 million years of life lived with a disability in 2010, an increase from 65.5 million years of life in 1990 . However, during this time frame, the prevalence of anaemia decreased from 40.2% to 32.9% . The difference in the incidence and prevalence of anaemia is likely to be due to increasing global population and increased survival among those with chronic, often inflammatory, diseases .
In 2011, the global prevalence of anaemia was 38% in pregnant women (32.4 million women) and 29% in all non-pregnant women (496 million women) . Therefore, a worldwide total of 528 million women of reproductive age are anaemic, of which 20 million are severely affected . There are wide variations in global prevalence reflecting economic status and associated nutritional deficiencies, but no country is exempt .
Given the magnitude of its worldwide prevalence, the World Health Organization (WHO) included a 50% reduction in anaemia for women of reproductive age as one of its six global nutritional targets for 2025 . The aim is to increase the identification and understanding of anaemia in women and increase prevention and management .
Worldwide the most common cause of anaemia is ID , accounting for approximately 50% of cases . Furthermore, the prevalence of ID is at least double that of iron deficiency anaemia (IDA), with more than 2 billion people affected . Other common causes of anaemia include haemoglobinopathy, schistosomiasis, parasites , other micronutrient deficiencies (such as vitamin B 12 , folate and riboflavin) and acute and chronic infections (HIV, cancer and tuberculosis) . These conditions often co-exist with ID 9 . Uterine fibroids and other gynaecological conditions are respectively the 13th and 26th most common causes of anaemia worldwide . The prevalence of these gynaecological conditions peaks at a young age and decreases steadily as women age . From the age of 15 until old age, anaemia more commonly affects women than men .
In a recent European survey, one in 10 of the population sampled had or have had ID or IDA at some point in their lifetime. Forty percent of Europeans sampled during the survey felt that ID had negatively affected their family life. Furthermore, time from initial symptoms to diagnosis was 2.5 years, and even with a diagnosis, 1 in 10 respondents did not receive medical management .
When treating women with heavy menstrual bleeding (HMB), we focus on the underlying causes of their blood loss and offer medical and surgical options to reduce this bleeding. We may check for anaemia, but rarely implement timely and appropriate treatment for ID. This study will consider iron metabolism and its importance in the body’s physiological processes, the aetiology and assessment of ID and IDA and our role in the management of these conditions.
Iron metabolism and its role in the body’s physiological processes
Iron is crucial for cellular functions including respiration, oxygen transport, DNA synthesis, energy production and cell proliferation . It mediates electron transfer with iron acting as an electron donor in the ferrous state and an acceptor in the ferric state. However, excess iron is toxic. To ensure iron requirements are met but toxicity is prevented, a tightly regulated homeostatic system operates to maintain levels within normal ranges. The controller of this system is the peptide hormone, hepcidin ( Figure 1 ).
Hepcidin is an acute-phase reactant that is primarily synthesised in the liver. In response to high circulating and tissue levels of iron, the expression of hepcidin increases. This also occurs when there is an ongoing inflammatory process or infection resulting in a reduced iron supply and a functional ID/IDA . Conversely, the transcription of hepcidin is inhibited in ID, tissue hypoxia and increased erythropoiesis with the aim of facilitating absorption of iron in the gut and release of iron from tissue stores . Circadian rhythm also affects hepcidin release , with an increase throughout the day associated with a fall in serum transferrin saturation.
Typically, there are 3–4 g of iron in the adult body of which two-thirds is found in haemoglobin as haem iron. There is no process for the active excretion of iron from the body. Daily 1–2 mg of iron is lost passively as sweat and shedding of cells from the skin and gastrointestinal tract . Menstruating women lose on average an additional 1 mg per day .
As the plasma iron continues to be consumed for haemoglobin synthesis, the plasma iron levels decrease and hepcidin production abates, completing the homeostatic loop. (Reprinted with permission from Intrinsic LifeSciences LLC, La Jolla, CA, USA: http://www.intrinsiclifesciences.com/iron_reg/) .
Approximately 40–60 mg of iron is recycled daily . Within the gut, absorption is limited to 1–2 mg per day (increasing to 6 mg in the third trimester of pregnancy) with the remainder of iron requirements met by recycling haem following the breakdown of erythrocytes by macrophages mainly in the spleen. This haem is bound to a plasma glycoprotein, transferrin, and transported to the bone marrow.
Hepcidin is crucial for regulating both gut iron absorption and erythrocyte recycling. If iron has been taken up by enterocytes but is not required, hepcidin prevents the entry of iron into the circulation by reducing the expression of ferroportin, a transmembrane protein than transports iron from the inside to the outside of a cell. Iron therefore remains in the enterocytes and is lost when these cells are sloughed off. Similarly, if recycled iron contained within macrophages is not needed, then hepcidin reduces the expression of ferroportin and iron again does not re-enter the circulation .
Hepcidin production decreases with acute blood loss, which increases importation of iron by ferroportin. In ID, hepatic production of transferrin and expression of transferrin receptors by the bone marrow and other tissues increases . Some of the iron from erythrocyte breakdown remains in macrophages as ferritin or as the water-soluble form of iron, hemosiderin. Levels of hepcidin are low in pre-menopausal, menstruating women and return to approximate parity with men in the post-menopausal period.
In normal circumstances, iron loss is compensated by dietary intake. Recommended daily intake (RDI) of iron for men is 8 mg/day, 18 mg/day for women and 27 mg/day in pregnancy. There are two forms of iron in the diet, haem iron from animal sources and non-haem iron from cereal and vegetable sources, the former being two to three times more readily absorbed from the gut than the latter .
Iron is primarily absorbed in the duodenum and upper jejunum. It is postulated that absorption of haem iron occurs through the intestinal haem iron transporter (HCP1) on the surface of enterocytes . This transporter is up-regulated in hypoxia and ID . Pancreatic enzymes play a role in freeing haem from globulin in the intestinal lumen prior to uptake by enterocytes . Non-haem iron is better absorbed in its ferrous form (Fe 2+ ) than in its ferric form. To optimise absorption, ingested ferric iron (Fe 3+ ) is reduced to Fe 2+ by stomach acid, ingested ascorbic acid, ferric reductase on the brush border and duodenal cytochrome b (DCYTB) . The absorption of non-haem iron is decreased by tannins and phytates (grains) . Germination and fermentation of cereals and legumes reduces their phytate content and thereby increasing absorption of iron . Entry of iron in its ferrous form into enterocytes from the intestinal lumen is mediated by the divalent metal transporter 1 (DMT1) . Expression of DCYTB and DMT1 are also increased in ID .
Once in the enterocyte, iron may be stored as ferritin or transported by ferroportin-1, located on the basal membrane, into the blood. Hephaestin (a copper-dependent ferroxidase) and ceruloplamin reoxidise Fe 2+ to Fe 3+ to assist its transportation by transferrin, an iron-binding protein, in the plasma . Hepcidin decreases iron transfer into the blood by binding with ferroportin-1 on the enterocytes internalising and degrading ferroportin-1. The iron contained within the enterocytes is then lost through sloughing ( Table 1 ).
| Hepcidin | 25-amino acid peptide hormone that regulates iron uptake and release from stores in response to circulating and tissue levels of iron. |
| Ferroportin | Transmembrane protein that exports iron into the blood from enterocytes and macrophages. |
| Ferric iron (Fe 3+ ) and Ferrous iron (Fe 2+ ) | Iron is essential for cellular respiration. In the ferrous state, iron acts as an electron donor, while in the ferric state, it acts as an acceptor. The ferrous form is better absorbed from the gut; therefore, the ferric iron is reduced to ferrous iron in the gut. |
| Ferritin | Main storage protein for iron. Found in all cells and bodily fluids, the highest concentration being found in hepatocytes. Serum ferritin is a marker of total iron stores in those with no chronic illness. |
| Transferrin | Iron-binding protein mostly produced by the liver; it acts as an intercellular transporter for iron, which is immediately available for uptake from the circulation by individual cells. Approximately 3 mg of total body iron is bound to transferrin at any one time. |
Within the blood, the high affinity of transferrin for ferric iron means there is effectively no free iron in the plasma . The amount of total body iron bound to transferrin at any one time is small (∼3 mg of the 3–4 g of total body iron) .
Iron is stored as ferritin, which is present in all cells and body fluids. Ferritin is a protein complex with the highest concentrations found in the liver (containing a third to a quarter of the body’s total iron) , spleen and bone marrow. These iron stores serve as a reservoir to meet future demand. While most ferritin is intracellular, a small amount can be found in serum, which correlates with total iron stores unless there is underlying inflammation, cancer or renal failure.
Clinical presentation
ID/IDA are chronic conditions that may be asymptomatic. Symptoms can include weakness, fatigue, irritability, hair loss, poor concentration and poor work performance, resulting from reduced enzyme activity and oxygen delivery to tissues . Many of these symptoms are also associated with HMB .
There is a higher prevalence of constant tiredness in young and middle-aged women with ID (67% and 63%, respectively) compared with those without ID (45% and 48%, respectively) . In a recent European survey, tiredness and fatigue were the symptoms that resulted in >50% of participants seeking advice from a medical professional. Furthermore, >60% of participants reported that their ID had negatively affected their ability to concentrate .
Women with ID may also complain of cold intolerance, palpitations, dizziness, headache, exercise-associated dyspnoea, restless legs and pica. Pica is an appetite for substances that are not a food source such as ice, soil or paper products . In severe IDA, tachycardia and cardiac failure may occur.
The symptoms accompanying ID and IDA depend on the rapidity with which the condition develops. For example, in the case of a chronic slow blood loss, the body adapts to the gradually declining levels of iron and slowly worsening anaemia resulting in few symptoms. Those which do occur in this situation are typically fatigue and dyspnoea.
On examination, signs of chronic IDA, including skin and conjunctival pallor, atrophic skin or koilonychia (spoon-shaped nails) may be seen. Patients may report painful cracking at the corners of the mouth identified as angular stomatitis. The classical findings of Plummer–Vinson syndrome, including dysphagia, oesophageal web and atrophic glossitis (inflammation of the tongue resulting in a smooth surface and a pale or red appearance to the tongue) are now rarely seen .
IDA in pregnancy is associated with maternal and neonatal morbidity and mortality with an increased risk of prematurity, low birth weight and peripartum blood loss . The mother is more susceptible to infection together with increased severity of that infection .
A meta-analysis of 20 studies showed that ID (without anaemia) also affects performance and work capacity . Furthermore, up to 50% of participants in a recent study reported that ID negatively affected their working life, leading to concerns regarding its potential effect on their concentration and productivity . Iron supplementation helps to improve these symptoms .
Aetiology of ID/IDA
RDI of iron for women of reproductive age is 18 mg, although the median is 12 mg to combat loss due to menstruation. ID/IDA occurs when loss or requirements exceed absorption. The causes of ID/IDA are often multifactorial . In general, there are four broad causative categories: increased loss of iron, decreased intake of iron in the diet, decreased absorption of iron from the gut and an increased iron requirement (see Table 2 ). Blood loss is an important cause of ID/IDA, as there is 0.5 mg of iron in every millilitre of blood . Compensatory mechanisms can increase iron absorption but cannot keep pace once iron loss exceeds 5 mg/day . This iron deficiency results in a reduced erythrocyte mass, which in turn stimulates erythropoiesis and consequently leads to ID/IDA.
| Cause | Example conditions |
|---|---|
| Physiological | Increased demand in infancy, adolescents, pregnancy, menstrual loss, blood donation, endurance sports |
| Environmental | Insufficient intake due to poverty, malnutrition, diet (vegan, vegetarian, iron-deficient diet) |
| Pathological | |
| Decreased absorption | Coeliac disease, atrophic gastritis, gastric and intestinal bypass, Helicobacter pylori colonisation, inflammatory bowel disease |
| Chronic blood loss | Gastrointestinal tract – oesophagitis, erosive gastritis, partial gastrectomy, peptic ulcer disease, malignancy, inflammatory bowel disease, haemorrhoids, hookworm infestation. Genitourinary tract – heavy menstrual bleeding, postpartum haemorrhage, intravascular haemolysis Systemic – hereditary haemorrhagic telangiectasia Eating disorders, Munchausen’s syndrome, chronic schistosomiasis |
| Drug related | Proton pump inhibitors (impairs absorption of iron), non-steroidal anti-inflammatory drugs, salicylates, glucocorticoids, anticoagulants |
| Genetic | Iron-refractory iron deficiency anaemia |
| Iron restricted/erythropoietic | Treatment with erythropoiesis-stimulating agents, anaemia of chronic disease/functional IDA, chronic kidney disease |
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