Iron deficiency E61.1

Synonyms

Iron deficiency; pallor; iron deficiency; ID;

First author

Hepcidin, a peptide hormone that controls iron absorption and plasma levels of iron, was discovered in 2000 (McCann 2016), with genetic localization in 2003 by Maryweather- Clarke and Roetto (Barton 2010).

Iron deficiency (ID) refers to a deficit of total body iron (Balletshofer 2013).

General information

Laboratory chemistry defines iron deficiency as:

- Ferritin 30 - 99 ng / ml

or

- Ferritin 100 - 300 ng / ml plus transferrin saturation < 20 (16%).

(Briese 2011)

Iron deficiency - depending on the severity - can lead to iron deficiency anemia (IDA) (Balletshofer 2013).

First, in iron deficiency, the iron stored in the RES as hemosiderin and ferritin is completely depleted. Only then does iron deficiency anemia occur. It is estimated that the period until the appearance of iron deficiency anemia in a healthy man with an iron-deficient diet or malabsorption lasts on average about 8 years (Hoffbrand 2003).

One differentiates in the iron stock in the human body between:

• heme iron:

This makes up the largest proportion with up to 70 %. It is bound to hemoglobin. One gram of hemoglobin contains about 3.4 mg of iron, an erythrocyte concentrate, for example, 250 mg of iron (Herold 2022).

• Depoteisen:

Depoteisen is stored intracellularly in the form of ferritin and hemosiderin. It accounts for approximately 18% (Herold 2022).

• Transfer iron:

This is bound as so-called transferrin and accounts for only 0.1 % of the iron stock (Herold 2022).

Iron deficiency is differentiated between absolute and relative iron deficiency.

• Absolute iron deficiency:

In absolute iron deficiency, the iron stores are depleted (Herold 2022). It is also called the "true iron deficiency" (Gafter- Gvili 2019).

• Functional iron deficiency:

In this case, storage iron is present, but the body cannot dispose of it (Herold 2022). Functional iron deficiency is predominantly due to increased hepcidin levels (Gafter- Gvili 2019).

Iron deficiency can be divided into different stages:

• Stage 1:

This is referred to as a reserve iron deficiency. Stage 1 is also referred to as prelatent or latent iron deficiency (Hallbach 2006).

In this stage, storage iron is decreased, functional effects are not apparent, i.e. Hb, MCV and MCH are normal (Behnisch 2021).

• Stage 2:

In this stage, complete consumption of reserve iron is found (Hallbach 2006) or due to inflammatory processes in the body, iron is retained from plasma primarily by hepcidin (Pasricha 2021).

The iron-deficient heme synthesis that now begins causes an increase in protoporphyrin in the erythrocytes. Ferritin saturation decreases < 16%, and ferritin itself is decreased. At least at the beginning of this stage, hemoglobin is still in the reference range (Hallbach 2006).

• Stage 3:

In the last stage, the Hb- value falls below the reference range. This is called manifest iron deficiency anemia (Hallbach 2006).

Iron deficiency is the most common deficiency in humans (Hallbach 2006).

Worldwide, about 25% of all people suffer from iron deficiency, of which about 80% are women. In Europe, about 10 % of women of childbearing age are affected and in developing countries > 50 % (Herold 2022). In men, iron deficiency is found in about 1 - 2 % (Gerok 2007).

In patients with chronic renal failure , the prevalence is 15.4%, increasing to 53.4% in the terminal phase (7.6% in the general population).

Patients with chronic heart failure are affected between 37% - 61% by iron deficiency with or without anemia (Elstrott 2020).

Iron deficiency represents the most common cause of all anemias at 80% (Herold 2022) and is the most prevalent malnutrition worldwide (Kasper 2015).

A distinction is made between absolute and functional iron deficiency.

• Absolute iron deficiency: This can be caused by
  • Iron losses: These are found to be the most common cause at 80%. Iron losses can occur due to
    • Bleeding from the digestive tract, e.g., ulcers, esophageal varices, erosive or HP-positive gastritis, colonic diverticulosis, carcinoma, gastric lymphoma, hemorrhoids, etc.
    • Bleeding from genitourinary tract, lungs, nose, gums, oropharynx, etc.
    • traumatic blood loss
    • blood losses due to hemodialysis (reach approx. 2.5 l / year)
    • surgically induced blood losses
    • blood donations
    • blood donors who do not substitute iron
    • menorrhagia
    • frequent blood collections
    • hemorrhagic diathesis (congenital or acquired due to medications such as ASA, anticoagulants, etc.)
    • intentionally induced bleeding by the patient in the context of mental disorders such as borderline disorder, Munchausen syndrome, etc.
  • Deficient iron absorption: Found, for example, in malassimilation syndrome, celiac disease, inflammatory bowel disease (CED), after gastric resection, etc. (Herold 2022).
  • Inadequate iron intake: This results from malnutrition or malnutrition and is the main cause of iron deficiency globally (Behnisch 2021). In industrialized countries, it can occur particularly in infants, children, and vegetarians (Herold 2022).
  • Increased iron requirement: This is particularly present in pregnant women, lactating mothers, athletes, during growth phases, and during Vit. B 12 supplementation due to Vit. B 12 deficiency anemia (Herold 2022).

• Functional iron deficiency: In functional iron deficiency, sufficient storage iron is present, but it is not bioavailable. This can occur due to
  • Hereditary iron-refractory iron deficiency syndrome (IRIDA = iron-resistant iron deficiency anemia [Behnisch 2021]).
  • Anemia of chronic disease (ACD):
    • Inflammatory anemias
    • Infectious anemias
    • Tumor anemias (Herold 2022)

In recent years, it has been shown that IDA also frequently occurs after bariatric surgery (Elstrott 2020).

Iron plays a crucial role in cellular respiration, oxygen transport and storage (Gafter- Gvili 2019).

Iron is found in the body in the following proteins:

• Heme- proteins:
  • Hemoglobin
  • Myoglobin
• Iron carboxylate protein:
  • Ferritin
• Iron- sulfur- protein:
  • Akonitins
• mononuclear proteins:
  • Superoxide dismutase (Kühne 2016).

Since iron is essential for the body, during evolution the organism has developed mechanisms to recycle the metal (Kühne 2016) by using the released iron for hematopoiesis after phagocytosis of erythrocytes by macrophages or storing it for further use (Gafter- Gvili 2019).

On the other hand, iron in abundance is toxic (Kühne 2016), as it can accept and transfer electrons, leading to severe oxidative stress and tissue damage (Gafter- Gvili 2019).

Regulation of iron balance occurs through adaptation and absorption. The peptide hormone hepcidin, which is mainly produced in the liver (Percy 2017), plays a crucial role in this process. It prevents iron transport by binding to the iron transporter ferroportin. Its ability to excrete iron is negligible (Gafter- Gvili 2019).

Iron deficiency - especially in the early stages - is usually asymptomatic. As soon as the iron deficiency becomes symptomatic, it is referred to as sideropenia (Herold 2022).

Symptoms in the case of prolonged iron deficiency or in the case of the iron deficiency anemia that then occurs, see d.

The diagnosis is made by laboratory chemical changes (see below) and, if necessary, by an oral iron absorption test (see below) (Hallbach 2006).

The etiology of iron deficiency should also be clarified with appropriate diagnostics by:

- Hemoccult test

- gastrointestinal diagnostics

- small intestine capsule endoscopy if the cause is unclear until then (Tischendorf 2019)

- urological examination

- gynecological examination

- gum examination

- exclusion of intravascular hemolysis which can be found e.g. in paroxysmal nocturnal hemoglobinuria and autoimmune hemolysis (Herold 2022)

see also iron deficiency anemia

• Oral iron absorption test

This test is used to clarify an absorption disorder for iron (Hallbach 2006).

Test procedure:

The patient appears fasting for the examination. First, blood is taken to determine the serum iron level. Then the patient is given a drink containing 100 mg of iron (e.g. as an effervescent tablet of Lösferron). After 2 - 4 - 8 hours, blood is taken again.

Test result:

If iron absorption is possible without disturbance, there is a strong increase in serum iron. After 2 h a maximum is reached, which indicates a value at least three times higher than the fasting value. Subsequently, the value drops again. In patients with an absorption disorder for iron, the increase does not occur (Begemann 1999).

To determine an iron deficiency should be determined according to Halbach (2006):

• CBC:

MCV and MCH values are initially normal in iron deficiency. However, there is an anisocytosis at an early stage. It is not uncommon to also find thrombocytopenia (Bain 1997).

Even latent iron deficiency results in erythrocytosis triggered by erythropoietin due to a reduction in oxygen transport capacity (Gerok 2007).

• Transferrin:

Reference value 2.0 - 3.6 g / l (Schaenzler 2009).

• Serum iron:

Reference value 350 - 1,600 µg / l (Schmiedel 2010).

• Transferrin saturation:

Transferrin saturation indicates how much of the available transferrin has bound iron. The transferrin saturation is measured in %. The normal range is between 16 - 45 %. If the transferrin saturation falls below 10 %, one can assume a manifest iron deficiency anemia.

If the transferrin saturation is low (approx. 15 %) and the ferritin value is elevated at the same time, there is a functional iron deficiency (Hallbach 2006).

• Serum ferritin:

The normal value in women is between 25 - 250 µg / l and in men between 30 - 300 µg / l (Schmiedel 2010).

Ferritin represents a semi-quantitative indicator of storage iron. However, it increases in inflammation and should therefore always be seen in conjunction with CRP (Chenot 2022). False low values for serum ferritin have not been described so far (Kaltwasser 2013).

Since microcytosis and hypochromia occur only in severe iron deficiency anemia, the reduction of serum ferritin concentration (so-called storage protein for iron [Kaltwasser 2013]) is of crucial importance.

However, the sensitivity is low in chronic diseases (Hallbach 2006). Similarly, an increase in ferritin can also occur in chronic liver disease.

In chronic renal dysfunction, iron deficiency cannot be diagnosed with ferritin as a single parameter, since there are disturbances in iron utilization and iron excretion from a GFR < 45 ml / min. Normal to high ferritin values with low transferrin saturation may then be present (Chenot 2022).

In any case, a lowered ferritin, regardless of renal or liver disease, is evidence of iron deficiency (Chenot 2022).

• Hepcidin:

There is no correlation between hepcidin, body size, body weight, and age.

Hepcidin is decreased in classical iron deficiency to increase the uptake of dietary iron and likewise the release of internalized or stored iron.

An increase in hepcidin synthesis is found when the supply of iron is blocked due to inflammation (Kiefel 2011).

• Soluble transferrin receptor (sTfR):

The sTfR should be determined especially in patients with chronic diseases. The reference value is between 0.81 - 1.75 mg / l. It always increases when the required iron is not available in sufficient quantities (Hallbach 2006).

• sTfR- Index:

The sTfR- index is calculated from the quotient of sTfR and the logarithm of the ferritin concentration. The normal sTfR- index is between 0.9 - 3.7 in women and between 0.9 - 3.4 in men. Thus, especially women with subclinical iron deficiency can be identified (Hallbach 2006).

• Reticulocyte hemoglobin (Ret- He):

Ret- He also allows early detection of iron deficiency. Values < 28 pg are considered to be the onset of iron deficiency (Hallbach 2006).

• Total iron binding capacity (TEBK).

An indirect measure of circulating transferrin is the "total iron binding capacity", also known as "total iron binding capacity" (TIBC) in Anglo-Saxon countries. The normal range is between 300 - 360 µg / dl (Kasper 2015).

see also iron deficiency anemia

With regard to the cause of iron deficiency, causal therapy should follow appropriate diagnosis, and appropriate iron substitutionshould also be initiated in cases of manifest iron deficiency (Herold 2022).

• Oral iron therapy

Iron substitution should be administered orally as initial therapy. Only divalent iron should be used for oral treatment, since the intestine can only absorb 10-20% of it (Herold 2022).

Bivalent iron is mainly absorbed in the duodenum and upper jejunum. Animal iron is already present as divalent Fe ++, trivalent iron ions from plant foods must first be reduced to divalent ions in the apical cell membrane (Behnisch 2021).

Dosage recommendation:

Iron lozenges e.g. on an empty stomach 1 x 100 mg Fe (II) / d or every 2nd day. With the 2-day administration, there is better tolerance and, due to the decrease in hepcidin, better absorption (Herold 2022).

Adverse effects:

- Gastrointestinal discomfort in the form of nausea, vomiting, constipation (Kasper 2015).

Duration of use:

The target value for ferritin is about 100 µg / l. Once this is reached, substitution should continue for another period of 3 - 6 months (Herold 2022).

Laboratory Controls:

Reticulocytes and Hb increase after only 1 week (Herold 2022), if the iron deficiency is severe. Serum ferritin should be checked after about 3 months (Behnisch 2021).

• Parenteral iron therapy

Indication:

The indication for parenteral iron substitution is in patients who

- cannot tolerate oral iron

- whose need is quite acute

- who are in constant need of iron (Kasper 2015)

- suffer from gastrointestinal diseases

- in severe renal insufficiency with large iron depots, but which cannot be mobilized (Wick 2013)

- In certain palliative situations, such as severe heart failure, (Lundgren 2018).

Here, parenteral iron administration in iron deficiency can relieve symptoms even in the absence of anemia (Lundgren 2018).

In recent years, parenteral administration has increased dramatically (Kasper 2015).

Iron from dextran-free high molecular weight stable complexes should be used for parenteral administration. Mixed injections should be avoided at all costs (Herold 2022).

Dosage Recommendation:

Iron (III) carboxymaltose such as Ferinject should be injected as an infusion up to 1,000 mg 1 x / week.

For iron (III) derisomaltose such as MonoFer, the maximum single dose is 20 mg / kg .

For iron (III) sodium gluconate complex such as Ferrlecit, the maximum single dose is 62.5 mg.

In the case of iron (III) hydroxide-sucrose complex such as Venofer, the maximum single dose that can be injected is 200-500 mg (Herold 2022).

The respective manufacturer's instructions should always be followed.

The injection should be administered slowly (follow the manufacturer's exact time instructions). A short infusion in 100 ml NaCl has been found to be best (Herold 2022).

Duration of use:

Total requirement is based on product information. Normalization of hemoglobin is the surest indicator of adequate substitution.

Serum ferritin should reach about 100 µg / l and transferrin saturation (TSAT) should be between 20 - 45% (Herold 2022). In any case, an increase in transferrin saturation to > 50 % should be prevented. If this persists for a long time, it is an indication of iron overload of the tissue. Since iron is toxic to cells, this condition should be avoided at all costs (Kasper 2015).

Laboratory Checks:

The earliest laboratory control is recommended 8 - 12 weeks after the last iron administration, as false positive values are indicated before that (Herold 2022).

Iron supplementation can also be given as:

• Erythrocyte transfusion (Kasper 2015).
• Erythropoiesis-stimulating agents (Metzgeroth 2015).

For more details see iron deficiency anemia.

I have no information on the prognosis of iron deficiency alone. Prognostic statements are only possible in the presence of iron deficiency anemia. For more details, see iron deficiency anemia.

Interactions of iron preparations:

Iron should not be taken simultaneously with, for example, antacids, colestyramine, tetracyclines, certain foods, and tea, since mutual absorption disturbances may occur (Herold 2022). From there, fasting intake without milk, tea, or coffee is recommended (Behnisch 2021).

Iron tablets:

- Are shadowing in the radiograph and can easily be mistaken for lithiasis

- can stain the stool black

- may also cause blackening of the tongue when dissolved orally

- in therapeutic doses, after prolonged use, can lead to iron overload in alcoholics, chronic liver disease patients and patients with hemochromatosis

- are toxic to children and can cause life-threatening conditions. The lethal dose is about 3 g of iron II sulfate. Therefore, iron preparations should always be kept away from children (Herold 2022).

1. Bain B J, Huhn D (1997) Roche basic course in haematological morphology. Blackwell Wissenschafts- Verlag Berlin / Vienna / Oxford / Edinburgh / Boston / London / Melbourne / Paris / Tokyo 202 - 203.
2. Balletshofer B, Claussen C D, Häring H U (2013) Hematology, rheumatology and dermatology: case-oriented introduction to clinical medicine. Georg Thieme Verlag Stuttgart 28
3. Barton J C, Edwards C Q, Phatk P D, Britton R S, Bacon B R (2010) Handbook of iron overload disorders. Cambridge Medicine University press 2
4. Begemann M (1999) Practical hematology: clinic, therapy, methodology. Georg Thieme Verlag Stuttgart / New York 665
5. Behnisch W, Muckenthaler M, Kulozik A (2021) AWMF guideline: iron deficiency anemia. Registration number 025 - 021
6. Briese V (2011) Medicinal products and food supplements in pregnancy and lactation: handbook from A - Z. Walter de Gruyter Verlag Berlin / New York 38
7. Burdach, S. (2007) Hematology and oncology. In: Schölmerich J, Burdach S, Drexler H, Hallek M, Hiddemann W, Hörl W H, Klein H, Landthaler M, Lenz K, Mann K, Mössner J, Müller- Ladner U, Reichen J, Schmiegel W, Schröder J O, Seeger W, Stremmel W, Suttorp N, Weilemann L S, Wöhrle J, Zeuner R A. Medical Therapy 2007 | 2008. Springer Verlag Berlin, Heidelberg. 1850 - 1860
8. Chenot J F, Scherer M (2022) General medicine. Elsevier Urban und Fischer Verlag Germany 325 - 332
9. Elstrott B, Khan L, Olson S, Raghunathan V, DeLoughery T, Shatzel J J (2020) The role of iron repletion in adult iron deficiency anemia and other diseases. Eur J Haematol. 104 (3) 153 - 161.
10. Flaschenträger B, Lenartz E (1954) The metabolism. Springer Verlag Berlin / Göttingen / Heidelberg 399
11. Gafter- Gvili A, Schechter A, Rozen- Zvi B (2019) Iron deficiency anemia in chronic kidney disease. Acta Haematol. 142 (1) 44 - 50
12. Gerok W, Huber C, Meinertz T, Zeidler H (2007) Internal medicine: reference work for the specialist. Schattauer Verlag 59, 69
13. Hallbach J (2006) Clinical chemistry and hematology for the beginner. Georg Thieme Verlag Sturrgart / New York 239 - 240
14. Herold G et al (2022) Internal medicine. Herold Publishers 33 - 38
15. Hoffbrand A V, Pettit J E, Moss P A H, Hoelzer D (2003) Basic course in hematology. Blackwell Verlag Berlin 31 - 36
16. Kasper D L et al (2015) Harrison's Principles of Internal Medicine. Mc Graw Hill Education, 625 - 629
17. Kiefel V (2011) Transfusion medicine and immunohematology: basic principles - therapy - methodology. Springer Verlag Berlin / Heidelberg 115 - 119
18. Kühne T, Schifferli A (2016) Compendium of pediatric hematology. Springer Verlag Berlin / Heidelberg 13 - 19
19. Lundgren C et al (2018) Drug therapy in the elderly. Elsevier Urban and Fischer Publishers 104 - 105.
20. McCann S R, Gardner- Thorpe C (2016) A history of haematology: from Herodotus to HIV. Oxfort University Press 151
21. Metzgeroth G, Hastka J (2015) Iron deficiency anemia and anemia of chronic diseases. The Internist (56) 978 - 988
22. Pasricha S R, Tye- Din J, Muckenthaler M U, Swinkels D W (2021) Iron deficiency. Lancet 397 (10270) 233 - 248
23. Percy L, Mansur D, Fraser I (2017) Iron deficiency and iron deficiency anaemia in women. Best Pract Res Clin Obstet Gynaecol (40) 55 - 67.
24. Schäfer S (2017) First description of the prognostic relevance of iron deficiency in acute coronary syndrome: results of the AtheroGene study. Press release DGK 08 / 2017
25. Schaenzler N, Bieger W P (2009) The great GU compass: laboratory values Gräfe und Unzer Verlag Germany 164.
26. Schmiedel V (2010) QuickStart nutrient therapy. Hippokrates Verlag Stuttgart 138
27. Schwabe U, Paffrath T (2016) Drug prescription report 2016: current data, costs, trends and comments. Springer Verlag Berlin / Heidelberg 268
28. Wick M, Pinggera W, Lehmann P (2013) Clinic and laboratory - iron metabolism and anemia: new concepts in renal and tumor anemias. Springer Verlag Vienna 80