Physicians' Academy for Cardiovascular Education

Iron deficiency without anemia affects multiple cellular processes

Iron deficiency beyond erythropoiesis: should we be concerned?

Musallam KM and Taher AT - Curr Med Res Opin. 2018 Jan;34(1):81-93

Iron has a broad range of roles in normal cellular function, and it serves as a cofactor for intracellular processes. At high concentrations, however, iron is potentially toxic. The body has no means to actively excrete excess iron. A sophisticated system for iron homeostasis normally maintains an optimal balance between adequate dietary iron absorption and iron loss.

Dietary iron that is absorbed from the gastrointestinal (GI) tract is bound to the protein transferrin and transported between cells. The liver-derived peptide hormone hepcidin regulates systemic iron homeostasis, while the intracellular iron homeostasis is regulated by the iron-regulatory protein/iron-responsive element system. These two regulatory systems are finely coordinated. The balanced iron homeostasis can, however, be disturbed easily. Iron deficiency can be the result of insufficient dietary iron intake, or of abnormal iron absorption, loss, metabolism or body distribution, due to disease. Iron deficiency can be absolute (iron stores are empty) or functional (iron stores have sequestered iron).

Iron deficiency is common in developing countries due to poor nutrition and parasitic infections. Other groups at risk include those in whom rapid growth or expanding erythropoiesis takes place, such as young children and adolescents, and elderly, and metabolic demand is high in the second and third semester of pregnancy. Numerous disease conditions can also cause iron deficiency, including disease states characterized by chronic inflammatory states. Chronic inflammation can lead to elevated levels of hepcidin, which inhibits both iron uptake from the gut and export of stored iron from macrophages and hepatocytes, resulting in limited availability of iron for cellular functions. Acute or chronic blood loss can also overwhelm the body’s limited ability to increase iron absorption in an attempt to compensate.

Erythropoiesis is the largest need for iron: about 70% of iron in the adult human body is found in the erythropoid compartment; within heme in hemoglobin in red blood cells. Iron deficiency is the leading cause of anemia. Anemia is the most readily recognized effect of iron deficiency, but it has become clear that iron deficiency in the absence of anemia also has unfavorable consequences. This article summarizes the key implications of iron deficiency, beyond erythropoiesis.

Mitochondrial function

//Biosynthesis// | Mitochondria are responsible for biosynthesis of heme and iron-sulfur clusters. These are essential components of proteins, and required for many enzymatic functions. Because of the importance of this biosynthesis, most of the available iron goes to mitochondria. Impaired production of heme or iron sulfur clusters can have various downstream consequences.

//Energy metabolism// | Energy metabolism and biosynthesis of essential compound critically depend on iron. Iron is essential for both heme-containing and iron-containing non-heme enzymes, including NADH dehydrogenase. Iron is thereby essential for generation of adenosine triphosphate (ATP) from adenosine diphosphate (ADP).

//Clinical effects// | Reduced cellular oxidative capacity and other effects on the mitochondria may explain the fatigue observed in non-anemic individuals with iron deficiency. Indeed, iron therapy can improve fatigue in those with low ferritin levels, but normal hemoglobin concentrations.

Effects of iron deficiency on myocardial function

The myocardium is particularly vulnerable to effects of iron deficiency, due to its high energy demands. In patients with stable chronic heart failure (CHF), those with iron deficiency but adequate hemoglobin levels, showed lower exercise capacity than iron-replete individuals. Administration of intravenous (IV) iron has been described to improve disease severity and symptoms in iron-deficient CHF patients, with or without anemia. Observed improvements include improved functional class, exercise intolerance, renal function, fatigue and quality of life.

Cytochrome P450 enzymes (CYP)

Iron is present as heme in the CYP superfamily of enzymes and is essential for the oxidation of substrates. Humans have about 50 different CY450 enzymes, of which those in the mitochondria synthesize and metabolize endogenous compounds, while those in the endoplasmatic reticulum mostly metabolize exogenous compounds such as medication. Iron is essential for CYP450 function, but clinical data on the effect of iron deficiency on CYP450 activity is lacking.

DNA replication, repair and the cell cycle

Various key proteins involved in DNA replication and repair also require iron, for instance DNA polymerases, primases, helicases and ribonucleotide reductases (RNRs) use iron-sulfur clusters as cofactors to form active proteins. In addition to its role in DNA replication, iron is important for normal cell cycle progression and growth. Synthesis of various factors involved in cell cycle regulation can be inhibited if iron supplies are low, with cell cycle arrest as a potential consequence. The mechanisms underlying the role of iron in cell cycle control remain to be elucidated.

The immune system

An effective immune response also requires iron. Immune cells need iron as a cofactor in the production of enzymes that secrete factors that can eradicate intracellular pathogens. Transferrin receptors (CD71) that mediate iron uptake are expressed on the surfaces of T-cells, immature proliferating thymocytes and B-cells, which affects their function. The humoral or antibody-producing response seems less affected by iron deficiency, but T-cell immunity is particularly affected. The effects thereof on the risk of infection is less clear though, partly because it is difficult to disentangle the immunological effects from effects of concurrent malnutrition and other micronutrient deficiencies.

Brain development and neuronal functioning

Pre-clinical data suggest that iron plays a role in neurotransmission and brain development and maturation. Moreover, iron deficiency has been shown to affect myelination in mice. In humans, studies have assessed the neurobehavioral effects of iron therapy, most of which were conducted in those with iron deficiency anemia, rather than with iron deficiency alone. These studies have reported lower motor skills, slower neural conduction, and impaired brain and behavioral development. The cognitive impact of iron deficiency per se is less clear; a recent meta-analysis found no significant impact of iron deficiency in non-anemic individuals on educational attainment in children, or in mental and psychomotor development in infants and another meta-analysis found not improvement of cognitive outcomes in younger children who received iron therapy. Other studies did, however, report increased attention and concentration, irrespective of baseline iron status, in those receiving oral iron therapy, or a modest effect on cognition, IQ, and psychomotor skills in iron deficiency anemia.

A well-documented effect of iron deficiency on neuronal function is its contribution to restless leg syndrome (RLS). Severity of symptoms in RLS is inversely related to serum ferritin levels, and iron repletion therapy often resolves the condition.

Thyroid peroxidase

Thyroid peroxidase contains heme, and Is an enzyme essential for the synthesis and secretion of thyroid hormones. In developing countries, addition of iron to iodine supplements enhanced improvement in thyroid function and volume as compared with iodine alone. In Western countries, this has not been tested, thus it is unclear whether these observations apply to well-nourished individuals or in those with adequate iodine levels.

Other possible effects of iron deficiency

Some less advanced hypotheses have been developed on the effects of iron deficiency, including the role of iron in the function of the iron-binding glycoprotein lactoferrin in cutaneous wound healing. Chronic iron deficiency may contribute to development of bone complications, possibly via the vitamin D activating role of iron. Both pathological iron accumulation and iron deficiency can increase oxidative stress, although most of the evidence has been gathered in the context of anemia.

Clinical implications

//Diagnosis// | To detect absolute iron deficiency, serum ferritin is considered the most sensitive and specific test. A cut-off value of 30 ng/mL seems appropriate for the general population, but no widely accepted cut-off value exists for those with iron deficiency without anemia. When iron availability can be insufficient, functional iron deficiency can be identified by measuring transferrin saturation (TSAT) and ferritin. A lower threshold of 100 µg/L for serum ferritin and/or a threshold for TSAT of 20% are considered appropriate in chronic inflammatory conditions, but cut-off values vary between guidelines.

//Treatment// | Iron deficiency in the absence of anemia merits intervention, even if there are resolvable direct causes. Until iron repletion is achieved, appropriate treatment should be started. Oral iron is often given, although intestinal absorption of iron is low. Absorption may be improved by using lower doses and avoidance of twice-daily dosing. In functional iron deficiency, absorption is particularly inhibited; thus oral iron has a low effectiveness. GI side-effects and a metallic taste compromise adherence.

IV iron can yield iron repletion more efficiently and faster, especially in those with inflammatory conditions. GI uptake is circumvented, and GI side-effects are avoided. Adverse events with IV iron are generally minor, infrequent and short-lasting. The risk for hypersensitivity reactions forms the major concern, which may be serious or potentially fatal. Moreover, recently a concern has been raised on the risk of transient hypophosphatemia, which might induce more lasting effects leading to bone complications.

Thus, iron deficiency may affect a broad range of cellular processes. It should be considered a condition in its own right, rather than a marker for anemia, as it is associated with numerous symptoms that are not related to anemia. Management of iron deficiency can prevent progression to iron deficiency anemia. Standard care of patients at risk for iron deficiency should include detection and appropriate treatment of iron deficiency.

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