DÄ internationalArchive49/2021The Evaluation of Iron Deficiency and Iron Overload

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The Evaluation of Iron Deficiency and Iron Overload

Dtsch Arztebl Int 2021; 118: 847-56. DOI: 10.3238/arztebl.m2021.0290

Gattermann, N; Muckenthaler, M U; Kulozik, A E; Metzgeroth, G; Hastka, J

Background: In the western world, 10–15% of women of child-bearing age suffer from iron-deficiency anemia. Iron overload due to chronic treatment with blood transfusions or hereditary hemochromatosis is much rarer.

Methods: This review is based on pertinent publications retrieved by a selective search on the pathophysiology, clinical features, and diagnostic evaluation of iron deficiency and iron overload.

Results: The main causes of iron deficiency are malnutrition and blood loss. Its differential diagnosis includes iron-refractory iron deficiency anemia (IRIDA), a rare congenital disease in which the hepcidin level is pathologically elevated, as well as the more common anemia of chronic disease (anemia of chronic inflammation), in which increased amounts of hepcidin are formed under the influence of interleukin-6 and enteric iron uptake is blocked as a result. Iron overload comes about through long-term transfusion treatment or a congenital disturbance of iron metabolism (hemochromatosis). Its diagnostic evaluation is based on clinical and laboratory findings, imaging studies, and specific mutation analyses.

Conclusion: Our improving understanding of the molecular pathophysiology of iron metabolism aids in the evaluation of iron deficiency and iron overload and may in future enable treatment not just with iron supplementation or iron chelation, but also with targeted pharmacological modulation of the hepcidin regulatory system.

LNSLNS

Vital cellular processes such as energy acquisition or oxygen transport require an adequate supply of iron. Transferrin saturation (TSAT) is an important biomarker of iron availability. Iron deficiency is present if the TSAT is less than 20%, and iron overload if it exceeds 40%. At TSAT levels above 60%–70%, so-called free iron is formed, which mainly damages hepatic parenchymal cells. Plasma iron levels are regulated by the hepcidin/ferroportin system. Hepcidin is a peptide hormone produced in the liver. It circulates in plasma and binds to the iron export protein ferroportin, inducing its degradation. Ferroportin is expressed primarily in duodenal mucosa cells, liver cells, and macrophages; it mediates the regulation of dietary iron absorption (1–2 mg per day), iron release from the liver (as needed), and iron recycling in macrophages (20–25 mg per day). When adequate iron is available, the liver produces hepcidin, which blocks further iron absorption from food. When iron stores are empty, hepcidin production is inhibited, so that ferroportin-mediated iron export from the duodenal mucosal cells and the transfer of iron to transferrin can proceed unimpeded (1, 2).

Disorders in the hepcidin/ferroportin regulatory system cause diseases associated with iron deficiency or iron overload. In hereditary hemochromatosis (HH), too little hepcidin is produced. The most common form of HH is caused by mutations in the HFE gene; rarer forms of HH are due to mutations in the transferrin receptor (TfR)2, hemojuvelin (HJV), hepcidin, or ferroportin genes. The hepcidin deficiency resulting from these mutations leads to excess absorption of dietary iron (3). Hepcidin formation is also diminished in iron-loading anemias (4). For example, in β-thalassemia, mutations in both β-globin genes lead to insufficient production of normal hemoglobin and impaired red blood cell function. Without adequate transfusion therapy, the resulting hypoxia induces increased production of erythropoietin (EPO), which stimulates the proliferation of erythropoietic progenitor cells in the bone marrow in an attempt to compensate for the anemia. This attempt, however, is ineffective. When erythropoiesis is ineffective, hepcidin production in the liver is inhibited by erythroferrone (ERFE), which is produced in erythroblasts under the influence of EPO (5). ERFE inhibits the so-called bone morphogenetic protein/small-body-size mothers against decapentaplegic homolog 1 (BMP/SMAD) signaling pathway by binding and inactivating BMP cytokines, which are produced in hepatic sinusoidal endothelial cells (6). In β-thalassemia, ERFE increases iron uptake by downregulating hepcidin production in the liver. In contrast, the anemia of chronic disease (inflammatory anemia) is characterized by abnormally high hepcidin levels due to the effect of interleukin 6 (IL-6), which activates the hepcidin-regulating Janus kinase (JAK) / signal transducers and activators of transcription (STAT) signaling pathway in liver cells. The increased hepcidin levels block iron release from storage cells and intestinal mucosa cells and thereby lead to a decrease in transferrin saturation (TSAT), as is often seen in the setting of inflammation (6).

Regulation of systemic iron metabolism
Figure 1
Regulation of systemic iron metabolism

Aside from malnutrition and blood loss, there are also rare genetic conditions that cause iron deficiency. Mutations in the serine protease TMPRSS6 (transmembrane protease serine 6, or matriptase-2) elevate the hepcidin concentration, leading to iron-refractory iron-deficiency anemia (IRIDA). TMPRSS6 normally induces the degradation of HJV and thus lessens the activity of the BMP/SMAD pathway; TMPRSS6 mutations enhance signaling activity and raise hepcidin levels. In both inflammatory anemia and IRIDA, hepcidin inhibits the intestinal absorption of iron and the release of recycled iron from macrophages, making patients refractory to oral iron supplementation and less responsive to intravenous iron supplementation (7).

Learning objectives

This article is intended to enable readers to

  • understand the key elements of the regulation of systemic iron metabolism,
  • be able to diagnose three stages of iron deficiency on the basis of appropriate laboratory parameters, and
  • know the main causes of iron overload and its proper diagnostic investigation.

Iron deficiency

Clinical features

Around the world, approximately 40% of pregnant women and children under 5 years of age, as well as approximately 30% of non-pregnant women, suffer from iron deficiency due to malnutrition and from the resulting anemia (8, 9). Iron deficiency is also the most common cause of anemia in Europe, affecting 2%–6% of children (10) and 10%–15% of women of childbearing age (9). Vegetarian and vegan diets have become more widespread in recent years and are an increasingly common cause of iron deficiency (11). Chronic bleeding is another common cause, malabsorption syndromes are less common, and genetic disorders of iron absorption and iron homeostasis are rare.

The main manifestations of iron deficiency are pallor and fatigue resulting from hypochromic-microcytic anemia, which is characterized by anisocytosis in blood smears and by increased red cell distribution width (RDW) in electronic cell counting. Patients with severe iron deficiency may have oral fissures, diffuse alopecia, and atrophic glossitis, and sometimes pica, i.e., the compulsive ingestion of non-food items, such as soil (12). A growing number of studies indicate that iron deficiency may be associated with neurocognitive dysfunction and behavioral problems in both children and adults (13). It is the most common cause of hypochromic–microcytic anemia, and is also a treatable risk factor for heart failure with an adverse course (14, 15). In infants and young children, iron deficiency usually does not manifest itself in anemia until the second half of the first year of life, when the reserves laid down during gestation are depleted and rapid growth leads to an increased iron requirement. A second incidence peak occurs in girls during puberty, when the growth spurt coincides with blood loss from menstruation (12). Later on, pregnancy is the main risk factor for iron deficiency. A proper diet, preferably including meat, is recommended to prevent iron deficiency at times of increased need for iron, e.g., during puberty or pregnancy. Persons on a vegetarian or (especially) vegan diet should take care to supplement their diets with iron salts.

The clinical investigation must include a search for causes of blood loss leading to iron deficiency. Possible causes are hypermenorrhea, excessively frequent blood donation, or gastrointestinal bleeding; fecal occult blood should be tested for, and gastrointestinal endoscopy should be performed if indicated. Helicobacter pylori infection can also cause iron deficiency. Moreover, the long-term diminution of gastric acid production by proton pump inhibitors or histamine-2 receptor antagonists impairs iron absorption in the duodenum.

Classification

Negative iron balance leads first to a deficiency of stored iron (stage I), which is not yet harmful to the patient, at least in terms of blood counts. Iron deficiency becomes clinically relevant when there is too little iron to meet the needs of the erythropoietic precursors in the bone marrow: this is the stage of iron-deficient erythropoiesis (stage II). Finally, when the hemoglobin value falls below the lower limit of normal, the negative iron balance has reached stage III, or iron-deficiency anemia. This staging system is based on erythropoiesis because there are reliable parameters for assessing the iron supply to the erythropoietic system, at least in otherwise healthy individuals, while there are none at present for assessing the iron supply to other iron-dependent systems in the human organism. For these other systems, an inadequate iron supply is suspected if there are corresponding clinical manifestations, such as fatigue, lack of concentration, or hair loss, which improve after iron supplementation.

Diagnosis

Various „iron tests“ (Table 1) are available that provide different kinds information. The ferritin level reflects iron stores, but says nothing about iron supply to the erythropoietic system. For this, other parameters must be used, such as intra-erythrocytic zinc protoporphyrin (ZPP), soluble transferrin receptors (sTfR), hypochromic erythrocytes (HYPO), or reticulocyte hemoglobin (CHr). Low transferrin saturation is indirect evidence of an inadequate iron supply to erythropoiesis; in this situation, a hemoglobin level below the lower limit of normal as defined by the WHO (for women: 120 g/L; for men: 130 g/L) indicates iron-deficiency anemia. Through the use of multiple, complementary parameters, iron status can be adequately characterized and its clinical relevance assessed (Table 2 and diagnostic algorithm in Figure 2).

Diagnostic algorithm for patients with suspected iron-deficiency anemia
Figure 2
Diagnostic algorithm for patients with suspected iron-deficiency anemia
Laboratory parameters for the investigation of iron deficiency
Table 1
Laboratory parameters for the investigation of iron deficiency
Assessing iron status through the use of multiple, complementary parameters
Table 2
Assessing iron status through the use of multiple, complementary parameters

In iron-deficient erythropoiesis, hemoglobin production is diminished and eventually anemia is the result. Iron deficiency accounts for at least 50% of all cases of anemia around the world (16, 17) and must therefore always be considered at the top of the list of differential diagnoses, particularly in patients with hypochromic-microcytic anemia with low erythrocyte indices (MCV, MCH). Further differential diagnoses with this pattern of laboratory findings include congenital hemoglobinopathies, primarily the thalassemias.

What is the best screening test for iron metabolism in routine clinical practice? The WHO recommends measuring the serum ferritin level (SF). Ferritin is the only parameter that reflects iron stores and can thereby be used to detect iron deficiency in an early stage. An SF <15 μg/L is held to indicate a deficiency of stored iron. According to the WHO, the upper limit of the normal range for SF is 150 µg/L in women and 200 μg/L in men. The diagnostic utility of ferritin is limited, however, by the fact that it is also an acute phase protein. Inflammatory and neoplastic diseases and diseases of the liver elevate the serum ferritin level, potentially masking a concomitant iron deficiency. The lower limit of normal for SF has, therefore, been defined differently for different patient groups so that it can still serve as a useful screening test for iron deficiency: this lower limit is 100 µg/L in patients with heart failure, and up to 200 µg/L in dialysis patients (18, 19). In one study, patients with iron-deficiency anemia and hematologic or solid neoplasms had SF values above 100 µg/L in 50% of cases, and half of these even had values above 800 µg/L (20). Moreover, non-alcoholic steatohepatitis (NASH) and other advanced liver diseases canbe associated with secondary iron deposition in the liver and an elevated SF. SF is, therefore, not suitable overall as a screening parameter for iron deficiency in multimorbid patients.

It is of marginal clinical importance whether the iron stores are full or less than full, as long as they are within the normal range. What the physician wants to know is whether the patient’s anemia, and/or his or her symptoms, are due to iron deficiency. The laboratory parameters that are relevant to this question are those that reflect the iron supply to erythropoiesis and those that indicate iron-deficient erythropoiesis (21). The TSAT is the most commonly recommended parameter for this purpose, with values under 20% reflecting inadequate iron supply. The same threshold value has been incorporated in the clinical guidelines for patients with neoplasia, heart failure, or chronic kidney disease. Further evidence of iron-deficient erythropoiesis can be derived from the percentage of hypochromic erythrocytes with an MCH <28 pg (HYPO), which is determined by modern blood-counting devices. In individuals without iron deficiency this is less than 2.5%; values above 10% are considered proof of a deficiency in erythropoiesis. HYPO is considered the best indicator of iron undersupply in patients with renal anemia who are undergoing treatment with erythropoiesis-stimulating agents (ESA). A further very early parameter of iron-deficient erythropoiesis is CHr, which reflects the hemoglobin content of the reticulocytes that are currently being produced. A CHr value below 26 pg is considered abnormal. CHr can also provide early evidence of successful iron supplementation.

Two especially valuable parameters for monitoring the iron supply to erythropoiesis are soluble transferrin receptors (sTfR) and zinc protoporphyrin (ZPP). The sTfR concentration depends both on the activity of erythropoiesis and on iron status. Elevated sTfR values are seen both in increased erythropoiesis and in iron-deficient erythropoiesis. ZPP is formed when too little iron is supplied to erythropoiesis, by the incorporation of zinc into protoporphyrin IX instead of iron. An elevated ZPP concentration is, therefore, seen not only in iron deficiency in the strict sense, but also in all conditions that involve iron-deficient erythropoiesis. The ZPP concentration rises continually from the onset of iron-deficient erythropoiesis, thus enabling the latter to be quantified and its clinical significance to be assessed (Table 2); see also https://www.onkopedia.com/de/onkopedia/guidelines/eisenmangel-und-eisenmangelanaemie/@@guideline/html/index.html (July 2021; not currently available in English). Parallel measurement of ZPP and sTfR is useful for differential diagnosis because, unlike ZPP, the sTfR concentration does not rise in a patient with an iron utilization disorder (22).

Aside from iron deficiency and hemoglobinopathy, a further differential diagnosis in hypochromic–microcytic anemia is the anemia of chronic disease (ACD), also known as anemia of chronic inflammation (ACI). In the specialized literature, ACD is considered to be a common type of anemia, indeed the most common type among hospitalized patients and the elderly (23, 24). In this situation, the deficiency of iron supply to erythropoiesis is not very pronounced, and a normochromic–normocytic pattern is usually found (25). Nonetheless, in severe, protracted courses, inflammatory anemia can also be hypochromic–microcytic. ACD is demonstrated by an increase in stored iron and by decreased sideroblast content in the bone marrow, which reflects an iron utilization disorder. The laboratory tests that are usually obtained cannot reliably differentiate ACD from true iron deficiency. Serum iron and TSAT levels are low in both cases, and the serum ferritin level is too unreliable, especially in multimorbid patients. Where there is simultaneous elevation of CRP, ACD is generally assumed rather than truly proven, and is thus overdiagnosed. As mentioned, the additional measurement of ZPP and sTfR is essential for differential diagnosis, because ZPP is elevated in both cases, but sTfR is almost always normal in ACD. A high sTfR in a patient with ACD indicates that the patient is suffering from true iron deficiency as well. The parallel measurement of sTfR and serum ferritin is also useful, as an elevated TfR-F index (the quotient sTfR/log SF) can indicate iron deficiency even in the presence of inflammation (21).

Iron overload

Oxidative stress

As early as the 16th century, Paracelsus realized that “only the dose makes the poison.” Iron is no exception. Iron is needed for a multitude of biological processes, but can also have toxic effect because free iron changes easily between its divalent and trivalent forms and thus acts as an electron carrier, catalyzing biochemical reactions such as the Fenton reaction, in which oxygen radicals are produced. These reactive oxygen species (ROS) damage macromolecules such as proteins, DNA, and lipids, and consequently also organelles such as lysosomes and mitochondria. The damage at the molecular and cellular levels can eventually lead to organ dysfunction. Iron overload thus has a toxic effect in that excess iron is present in an unbound form, causing severe oxidative stress. When, at a TSAT of approximately 60%–70%, the iron binding capacity of transferrin is exceeded, “non-transferrin-bound iron” (NTBI) is formed. One fraction of NTBI is called labile plasma iron (LPI). LPI is both redox-active and chelatable. It can cross the plasma membrane and is taken up particularly readily by various cells, for example by cardiac muscle cells via voltage-gated calcium channels.

Clinical features

Diseases such as hereditary hemochromatosis and anemia requiring chronic transfusion therapy, such as the thalassemias, show that the consequences of iron overload can be multifarious (26, 27). Myocardial iron overload can result in heart failure and arrhythmias, and iron overload in the liver leads in the long term to fibrosis, later to cirrhosis, and even to the development of hepatocellular carcinoma (28). Endocrine organs are particularly sensitive to iron overload, so diabetes mellitus, hypothyroidism, or – in young patients with thalassemia major – hypogonadism may develop. Iron overload also promotes bacterial growth and thus infections. It also has vascular effects. Macrophages in the vascular wall can accumulate iron, leading to oxidative stress and reduced cholesterol export, resulting in increased plaque formation (29).

Classification

Both congenital and acquired diseases exist that lead to iron overload. As the Box showing the etiological classification makes clear, the division between congenital and acquired is not identical with the division into primary and secondary hemochromatosis. Positing a further subdivision for secondary siderosis (as iron deposition without tissue damage) seems to us unnecessary, since the point at which tissue damage is detected depends on the sensitivity of the examination techniques. This conceptual distinction is not made in the English-language literature either (with the exception of local hemorrhage-related iron deposition, such as in pulmonary siderosis).

Etiological classification of iron overload disorders
Box
Etiological classification of iron overload disorders

Bei den erblichen Erkrankungen handelt es sich einThe hereditary diseases are made up of, first, various types of hereditary (primary) hemochromatosis (HH), which are caused by either a disorder of the hepcidin/ferroportin system or disordered iron transport (27) (eTable) and, second, the “iron-loading anemias,” which are due to ineffective erythropoiesis (30). These last are non-transfusion-dependent thalassemia (NTDT), congenital sideroblastic anemia, and congenital dyserythropoietic anemia.

Hereditary forms of systemic iron overload
eTable
Hereditary forms of systemic iron overload

Iron overload disorders with an acquired cause also include those due to ineffective erythropoiesis, especially myelodysplastic syndromes (MDS) (31), and also in general all acquired hematopoietic disorders that lead to long-term transfusion dependence—apart from MDS, these include for example primary myelofibrosis and aplastic anemia. With each unit of red cell concentrate, the patient receives at least 200 mg of iron. Since the organism has no physiological mechanism for excreting excess iron, a negative iron balance can only be achieved through the use of chelating agents.

Diagnosis

Serum ferritin

Serum ferritin (SF) generally remains proportional to the iron stored in macrophages, which in turn is a useful measure of total body iron. In patients with hereditary hemochromatosis, however, iron overload affects not the macrophages but the liver cells. SF levels then correlate with the latter, but may underestimate the concentration of iron in the liver (32, 33). As an acute-phase protein, SF is also elevated in inflammation. Extremely elevated levels are found in macrophage activation syndrome in the setting of secondary or primary hemophagocytosis. It is therefore recommended that when evaluating SF levels, inflammatory markers such as C-reactive protein (CRP) should be investigated at the same time. It is also important not to rely on a single SF value but to observe the trend over time (34). In patients with myelodysplastic syndrome with a long-term need for transfusion it was found that, after a median of 21 units of red cell concentrate had been given, median SF reached 1000 μµg/L (35).

Transferrin saturation (TSAT)

Measuring TSAT is another simple investigation, and in screening for HH it is even more sensitive than SF. A TSAT above 45% in women or above 50% in men should prompt further genetic testing in this direction (eTable). Highly elevated TSAT indicates the presence of iron overload related to NTBI- or LPI-mediated iron toxicity. A disadvantage is that serum iron fluctuates considerably over the course of the day, and the TSAT varies accordingly. Another influence arises from the disordered iron distribution seen with inflammation. In addition, production of transferrin and thus total iron binding capacity may be impaired in patients with liver disease and inflammation. The TSAT should be looked at together with the SF. It should be noted that when SF is elevated, the absence of elevated TSAT does not rule out iron overload, as this abnormal combination may occur in patients with a loss-of-function ferroportin mutation or aceruloplasminemia. During iron chelation therapy, the elevated TSAT is slow to regress and is therefore not a good parameter for follow-up (36).

Other laboratory investigations

Measuring serum hepcidin does not improve the estimation of iron overload because there is a correlation between hepcidin and SF (37). The same is true for measurements of NTBI and LPI, which can serve as surrogate parameters for iron-induced oxidative stress and are very rapidly affected by iron chelators but are not a suitable tool for estimating total body iron.

Diagnostic imaging

Measuring cardiac and hepatic iron has an essential role both in assessing impending complications and in guiding iron chelation therapy. Serum ferritin is of limited use in measuring iron overload (38). The iron content of the liver correlates better with total body iron. For noninvasive quantification, an MRI-based method is approved for use in the European Union (39) (Figure 3); it is suitable for a broad range of iron-loading disordersand is available at numerous facilities in Germany. Cardiac iron overload is an important special case because it correlates poorly with liver iron levels (40) but has prognostic significance and is important for guiding iron chelation therapy. It usually occurs in patients with thalassemia with a background of many years of transfusion therapy. MRI (T2*-weighted gradient echo sequence) is now the standard technique for measuring cardiac iron (e1). Very low relaxation times of less than 10 ms correlate with the onset of heart failure. These resource-heavy techniques for noninvasive quantification of iron overload are indicated in patients for whom these data affect management decisions, such as guiding iron chelation therapy in patients with long-term transfusion dependence or for risk assessment and treatment decisions in possible candidates for stem cell transplantation.

Measuring mean liver iron concentration using magnetic resonance imaging
Figure 3
Measuring mean liver iron concentration using magnetic resonance imaging

Discussion

When investigating cases of iron deficiency and iron overload, several parameters often need to be looked at simultaneously in order to identify the extent and cause of the problem. Some useful parameters, such as zinc protoporphyrin measurement, are not yet widely available. More detailed understanding of the hepcidin/ferroportin system as the central regulator of iron metabolism in the future will probably enable the treatment of iron metabolism disorders not just by iron substitution or iron chelation, but also by targeted drug manipulation of hepcidin regulation.

Conflict of interest statement
The authors declare that no conflict of interest exists.


Manuscript received on 10 February 2021, revised version accepted on 7 July 2021

Translated from the original German by Ethan Taub, MD, and Kersti Wagstaff

Corresponding author
Prof. Dr. med. Norbert Gattermann
Klinik für Hämatologie, Onkologie und Klinische Immunologie
Universitätsklinikum Düsseldorf
Moorenstr. 5, 40225 Düsseldorf, Germany
gattermann@med.uni-duesseldorf.de

Cite this as:
Gattermann N, Muckenthaler M, Kulozik AE, Metzgeroth G, Hastka J: The evaluation of iron deficiency and iron overload. Dtsch Arztebl Int 2021; 118: 847–56. DOI: 10.3238/arztebl.m2021.0290

Supplementary material

eReferences, eTable, case report:
www.aerzteblatt-international.de/m2021.0290

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Department of Haematology, Oncology and Clinical Immunology, Düsseldorf University Hospital: Prof. Dr. med. Norbert Gattermann
Department of Pediatric Oncology, Hematology, and Immunology, Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg University Hospital
Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Translational Lung Research Center Heidelberg, German Center for Lung Research, Heidelberg, German Center for Cardiovascular Diseases, Partner Heidelberg: Prof. Dr. phil. nat. Martina U. Muckenthaler
Department of Pediatric Oncology, Hematology, and Immunology, Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg University Hospital: Prof. Dr. med. Andreas E. Kulozik
III. Department of Hematology and Oncology, University Hospital Mannheim : Prof. Dr. med. Georgia Metzgeroth, Prof. Dr. med. Jan Hastka
Etiological classification of iron overload disorders
Box
Etiological classification of iron overload disorders
Regulation of systemic iron metabolism
Figure 1
Regulation of systemic iron metabolism
Diagnostic algorithm for patients with suspected iron-deficiency anemia
Figure 2
Diagnostic algorithm for patients with suspected iron-deficiency anemia
Measuring mean liver iron concentration using magnetic resonance imaging
Figure 3
Measuring mean liver iron concentration using magnetic resonance imaging
Laboratory parameters for the investigation of iron deficiency
Table 1
Laboratory parameters for the investigation of iron deficiency
Assessing iron status through the use of multiple, complementary parameters
Table 2
Assessing iron status through the use of multiple, complementary parameters
Hereditary forms of systemic iron overload
eTable
Hereditary forms of systemic iron overload
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