Iron deficiency ( ID) is the most prevalent nutritional deficiency and an important precipitant of anemia (iron deficiency anemia: FA). It is estimated that iron deficiency without anemia (IDHSA) at least doubles that of common FA. AF is the most common presentation of DH; Therefore, there is a misconception that the two terms are synonyms.
Iron deficiency (ID) is a broader term and refers to low iron stores that do not meet the body’s iron requirements, regardless of whether anemia is present or not.
Although HD reduces hemoglobin (Hb) synthesis, it is only classified as anemia once Hb levels fall below certain cutoff values, which the WHO has set at 130 g/l for males, 120 g/l for men. l for non-pregnant women and 110 g/l in pregnant women. However, symptoms of anemia, such as fatigue, may be present without anemic Hb levels.
Recognizing DHSA as a clinical diagnosis is crucial to ensure adequate treatment, especially for patients with chronic diseases, such as heart failure, in which DHSA may increase long-term mortality.
| Diagnostic definition of iron deficiency |
Ferritin is an indicator of iron stores and is the most sensitive and specific biomarker to evaluate HD . The WHO considers a ferritin level <15 µg/l in adults and <12 µg/l in children to be low. However, in clinical practice, when ferritin levels are 30 µg/, it justifies the study of DH.
Ferritin is an acute phase reactant that increases in serum during chronic inflammation. The cut-off values for ferritin in DH increase to 100 µg/l in states of chronic inflammation. Transferrin saturation levels (SATT) 20% also identify ID.
In chronic inflammatory conditions, when ferritin levels are 100 to 300 µg/l, SATT should be used to diagnose DH. Serum iron levels fluctuate throughout the day and should not be used for diagnosis. Other useful tests include hepcidin, soluble transferrin receptor, and reticulocyte Hb content, but they are not widely used. Although hepcidin is usually low or normal in absolute DH, it helps distinguish it from functional DH.
The soluble transferrin receptor is a valuable indicator of DH since, unlike ferritin, it is not affected by inflammation. It should be noted that performing this test takes too long and is not widely available. When Hb levels are normal, the low Hb content of reticulocytes allows early identification of DH in functional stores and hints at iron need, preanemia, and the risk of developing FA.
The distinction between AF and DHSA is based on the use of strict Hb cutoffs. However, clinicians should consider the fact that normal Hb ranges have been established using population data.
Essentially, what may be a normal Hb level for one person may be abnormal for another, especially if the patient has an Hb level in the low normal range but usual Hb levels are higher.
Patients with iron deficiency (ID) should be treated regardless of whether they are explicitly defined as anemic.
Hb cut-off ranges are useful but limitations must be taken into account while patient evaluation must be individualized.
| Causes of iron deficiency |
Iron is found in storage tanks and functional tanks. The storage tank is made up of the reticuloendothelial system, made up of the liver, spleen and ganglia. The functional deposits are made up of erythrocytes and cells of the bone marrow, cardiac muscle and skeleton. Iron is absorbed in the duodenum through specific transporters and, bound to transferrin molecules, it reaches functional and storage deposits.
Iron deficiency (ID) can be absolute or functional.
It is called functional DH when storage stores are deficient in iron due to reduced intake, increased needs, reduced absorption, or excessive loss. Absolute HD is also associated with low iron levels in functional stores.
In functional DH , the burden is chronic inflammation, causing the release of cytokines and hepcidin. The latter causes DH through blocking an iron exporter known as ferroportin. There are two ways this crash occurs. One, reducing the absorption of iron in the duodenum and another, causing iron retention within storage deposits.
This means that. Despite normal levels of iron within the storage stores, the functional stores are deficient in iron and cannot utilize the stored iron for the demands of vital body processes.
The causes of DH can be grouped into the following categories: inadequate dietary intake, increased body needs, reduced absorption, chronic inflammation, and chronic blood loss.
Inadequate intake may result from iron-deficient diets, such as the increasingly popular vegan diets, or from increased iron requirements, as seen in growing children and pregnant women. On the other hand, athletes who practice demanding sports have a higher iron requirement and are at greater risk of developing ID, mainly due to losses through urine and sweat, during physical activity.
Iron absorption occurs mainly in the proximal small intestine, for which the presence of sufficient gastric acid is required for the reduction of Fe3+ to Fe2+, which is more easily absorbed. Patients undergoing bariatric surgery are highly susceptible to DH due to areas of reduced surface absorption capacity and/or reduced gastric acid secretion.
Lower postoperative dietary iron intake further increases the risk of DH. Less commonly, Helicobacter pylori infection can cause DHF due to reduced iron absorption and blood loss.
Patients with autoimmune gastritis also suffer from loss of gastric acid secretion, so iron is not absorbed effectively.
On the other hand, chronic use of proton pump inhibitors or histamine-2 receptor antagonists may increase the risk of DH through a similar mechanism.
Consumption of coffee, tea, or calcium (in supplements or dairy products) has been reported to reduce iron absorption. The importance of these diets as causes of HD is sometimes overlooked.
Chronic inflammation , such as in celiac disease, inflammatory bowel disease (IBD), and heart failure, increases hepcidin production, blocking iron transporters and reducing absorption, leading to iron trapping within storage stores. . Ultimately, this results in a functional DH.
DH may also be due to significant or chronic occult blood loss , which is common in women with menorrhagia, and is further amplified in obesity and during rapid growth in adolescence, which can deplete iron stores. DH is also common in frequent blood donors and pregnant women.
Other causes include: nosebleeds, gastrointestinal bleeding (e.g., angiodysplasia), surgical procedures, injuries, accidents, and use of intrauterine devices, anticoagulants, or antiplatelets.
| Clinical features |
It is well established that iron plays an indispensable role in the synthesis of Hb and myoglobin. Less appreciated is its role in mitochondrial function , including the synthesis of cofactors and enzymes necessary for cellular respiration. Consequently, highly metabolic cells such as cardiac and skeletal muscle myocytes depend on iron for optimal function. DH has been shown to reduce aerobic respiration and citric acid cycle enzymatic activity in advanced heart failure.
Other studies have also demonstrated the negative impact of DH on cellular metabolism. Another trial of 40 chronic heart failure patients on DH demonstrated increased skeletal muscle energy after Iron supplementation. Although many cellular processes are iron-dependent, they are likely only affected in severe ID, where iron is likely present. More research is needed to further clarify the effects of DHSA on cellular processes and how its effects would be related to clinical presentation.
The symptoms of DH, such as fatigue and exercise intolerance, are nonspecific, making it difficult to identify whether the cause is DH or the chronic disease, such as heart failure, which may present with symptoms.
Hypothyroidism, depression, and exhaustion may also be responsible.
Furthermore, it is difficult to distinguish DHSA from absolute DH based solely on symptoms given their overlap; The main clinical difference is that the symptoms are more severe in absolute DH. A recent systematic review concluded that, in DHSA, iron supplementation improves subjective measures of fatigue.
In patients with DHSA who have coexisting heart failure or inflammatory bowel disease, intravenous iron supplementation improves symptom control and improves quality of life, respectively. However, the evidence on the effect of iron supplementation on physical activity, often assessed by maximal O2 uptake tests, is mixed.
Severe DH can also cause cardiac and skeletal myopathy, which is detrimental in heart failure. This is due to impaired elimination of reactive O2 species, increasing oxidative stress and thus weakening the heart muscle. Ultimately, atrophy of cardiac, peripheral, and respiratory muscles leads to reduced exercise tolerance and exertional dyspnea. In heart failure, mitochondrial function is already impaired, and overlapping effect of DH can be detrimental.
| Iron deficiency in pregnancy |
Absolute iron deficiency (ID) increases maternal morbidity as well as the risk of poor pregnancy outcomes including intrauterine growth restriction, prematurity, and low birth weight.
Compared with pregnant women without DH, pregnant women with decreased iron stores or DHSA in early pregnancy are more likely to develop pre- and postnatal DH and have a low birth weight newborn. Anemia is one of the late manifestations of DH. During fetal growth and when iron is scarce, it is directed mainly to the erythropoietic tissues, at the expense of the rest of the body.
Therefore, DH may exist in other organs such as the brain, not coinciding with Hb levels. DH has been associated with mental illness and impairment of neurocognitive functions, such as decreased memory and slower neural processing, which may be due to DH independently of anemia.
Postnatal ID is related to neonatal iron status and fetal iron load, and is associated with permanent cognitive and behavioral effects, which remain measurable until age 19 years, even with postnatal iron replacement.
Iron sufficiency is vital throughout pregnancy, especially from week 32 of gestation, when rapid myelination of the brain begins, and throughout childhood. Consequently, mothers should be screened and treated for their DH before conception.
Iron can be replaced during pregnancy with oral iron every 2 days in the first trimester, in order to improve maternal absorption. If ID persists, intravenous iron, which has been shown to be safe, should be administered in the second and third trimester. Furthermore, after birth, newborns should be examined and treated for their DH, to avoid permanent neurocognitive damage.
| Preoperative iron deficiency |
Unlike preoperative absolute DH, the effects of preoperative DHSA on surgical outcomes have not received sufficient attention. The objective of hematological management of patients goes beyond how to detect iron alterations after surgery, thus reducing transfusions and postoperative complications. However, recommendations often underestimate the importance of preoperative DHSA.
Preoperative DHSA in abdominal or cardiac surgery increases the risk of postoperative infection, fatigue, transfusion, and anemia. A recent trial found that short-term treatment with a combination of intravenous iron, erythropoietin α, vitamin B12, and folic acid reduced blood transfusions in patients with preoperative DHSA undergoing elective cardiac surgery.
Furthermore, preoperative supplementation with oral iron, vitamin C, and folic acid in non-anemic patients undergoing orthopedic surgery reduced blood transfusions. The British Committee for Standards in Hematology recommends iron supplementation for patients with DHSA (ferritin <100 µg/L and SATT <20%) who are planning to undergo surgery with an expected Hb loss of >30 g/L.
An international consensus statement on perioperative DH and anemia emphasized the importance of detection and management of DHSA before surgery. Elective surgery with expected significant blood loss should be postponed until the DH and/or anemia have been corrected, to reduce the risk of postoperative anemia. The recommendation is that oral iron be used when surgery is scheduled for more than 6 weeks; Otherwise, it is best to indicate intravenous supplements.
Collaboration between primary and secondary care physicians is very important for the effective management of preoperative DHSA. Ideally, testing should be performed in primary care, to avoid delays in surgery. The authors argue that in the future, awareness of DHSA should be raised among physicians, especially in primary care, which could reduce the prevalence of undiagnosed DHSA. This would minimize the risk of DHSA and DHA, in addition to improving the patient’s hematological management.
| Instructions for handling |
DHSA should be treated when it is barely identified, aiming for Ferritin 100 mg/l.
Treatment should be continued until ferritin levels have normalized and symptoms disappear. Patients should be counseled on diet and oral iron replacement. Intravenous iron replacement should be considered for symptomatic patients with refractory DHSA. Furthermore, ferritin levels should be monitored every 6 to 12 months after treatment, especially in menstruating women and those considering pregnancy.
Diet is important in the management of DHSA. Patients should try to consume meat, poultry or fish at least 5 times/week, with complementary whole grain products, legumes and vegetables. They may also be referred to a dietitian for detailed assessment and advice. However, dietary supplementation alone may not be sufficient to correct the deficiency, requiring replacement medications. Oral iron is associated with gastrointestinal side effects such as constipation, diarrhea, dyspepsia, and nausea, which have been associated with poor treatment adherence.
The use of single doses on alternate days rather than multiple doses on consecutive days results in greater absorption and better regulation of hepcidin levels in iron-depleted women.
The recommended oral dose is 28 to 50 mg iron/day or 100 mg every other day for 25 days. The goal is for patients to be contacted 1 week after the start of treatment to evaluate drug tolerance and change the formulation or dose if necessary.
Hb, ferritin, and C-reactive protein levels should be reviewed 6 to 8 weeks after initiation of treatment, in addition to red blood cell indices, to assess response to treatment. If oral supplementation is inadequate, intravenous iron replacement and referral to a specialist should be considered.
Once ferritin levels have been corrected, patients should be followed with blood tests every 6 to 12 months, with reintroduction of replacement if necessary. Intravenous iron is indicated when oral iron is ineffective and also in DHSA, to compensate for decreased absorption after gastric bypass, since the intestinal mucosa is damaged, and also in other chronic inflammatory conditions, such as heart failure, in those in which hepcidin is elevated.
Intravenous iron has been shown to be effective and well tolerated in DHSA, and may be more effective than oral preparations. About 1% of patients experience minor infusion reactions, requiring stoppage of the infusion and treatment of symptoms.
The severity of reactions is often exaggerated due to the risks associated with high molecular weight iron dextran, which has now been replaced by substantially safer formulations. In the UK they are low molecular weight iron dextran, iron sucrose, ferric carboxymaltose and iron isomaltoside (known in the US as ferric derisomaltose).
Ferumoxytol, which was withdrawn from European markets in 2015, remains available in the U.S. and has been shown to be safe. Excluding high molecular weight iron dextran, the risk of severe reactions is very low. However, it is essential to administer intravenous iron in a setting where such adverse effects can be adequately managed. As with oral iron, monitoring is essential.
| Conclusion |
Despite the simplicity of pathogenesis and treatment, DHSA often remains beyond the scope of clinical suspicion. It is important to not only spread awareness about the condition in the medical community, but also develop guidelines and protocols to assist physicians. This requires greater collaboration between medical specialists and physicians to identify and treat DHSA, especially preoperatively and in the context of pregnancy.
