Iron deficiency anaemia D50.9

Synonyms

Iron deficiency; pallor; sideropenia; iron deficiency anemia; IDA;

First author

In 1988, a recombinant human epoetin first came on the market (Schwabe 2016).

Iron deficiency anemia (IDA) is an anemia caused by iron deficiency. It represents a form of malnutrition (Kasper 2015). It is a hyporegenerative, microcytic and hypochromic anemia with - due to the reduction in the availability of iron - significant anisocytosis (Behnisch 2021).

Iron deficiency anemia is a hypochromic microcytic anemia characterized by a deficiency of hemoglobin in the erythrocytes (Metzgeroth 2015).

IDA 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 referred to as 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).

Anemia is caused by iron deficiency in about 50% of cases. This makes iron deficiency anemia the most common malnutrition worldwide (Kasper 2015).

The prevalence is highest in developing countries (Metzgeroth 2015).

Worldwide, about 25% of all people suffer from iron deficiency, of which about 80% are women. In Europe, approximately 10% of women of childbearing age are affected and >50% in developing countries (Herold 2022).

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 between 37% - 61% affected by iron deficiency with or without anemia (Elstrott 2020).

General information

Iron deficiency anemia is defined as an

• Hb < 13 g / dl in men and
• < 12 g / dl in women
• Serum ferritin < 30 ng / ml (Gafter- Gvili 2019).

In patients with chronic kidney disease (CKD), iron deficiency anemia is defined as follows:

• Transferrin saturation (TSAT) ≤ 20%.
• Serum ferritin ≤ 100 ng / ml or ≤ 200 ng / ml in hemodialysis.
• Hepcidin elevated (Gafter- Gvili 2019).

Iron deficiency represents the most common cause of all anemias, accounting for 80%. IDA can be caused in women of childbearing age especially by menstruation, gravidity and lactation. The daily iron requirement is 12 mg in men, 15 mg in menstruating women, and 30 mg in pregnant women (Herold 2022).

• 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 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 can occur especially in infants, children and vegetarians (Herold 2022).
  • Increased iron requirement: This exists especially in pregnant women, nursing mothers, athletes, during growth phases, and with 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 bodies, during evolution organisms have 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 plays a major role in this process. It prevents iron transport by binding to the iron transporter ferroportin. The ability to excrete iron is negligible (Gafter- Gvili 2019).

If there are symptoms due to the iron deficiency, it is called "sideropenia".

These can be:

• General symptoms of anemia:
  • Paleness of the skin (uncertain sign)
  • pallor of the mucous membranes (more sure sign)
  • Tachycardia: To compensate for the lack of oxygen, there is an increase in heart rate. This may lead to irreversible tachycardia-induced cardiomyopathy during vigorous exercise.
  • exertional dyspnea due to the decreased number of O2-carriers
  • general weakness
  • worsening of pre-existing heart failure
  • systolic murmur due to flow turbulence with increased cardiac output and decreased viscosity (Herold 2022)
• Skin and mucous membrane symptoms:
  • chronic recurrent aphthae in the area of the oral mucosa
  • dry skin
  • pruritus
  • diffuse hair loss
  • brittleness of nails
  • hollow nails (so-called koilonychia)
  • grooving of the nails
  • rhagades of the corners of the mouth (perlèche)
  • Plummer- Vinson syndrome (Herold 2022)
• Nonspecific neurological or mental symptoms:
  • Lack of concentration
  • headache
  • easy excitability
  • abnormal appetite (so-called pica)
  • Restless Legs Syndrome (RLS) (Herold 2022)

In the case of iron deficiency anemia in the fetal or early infant period, (controversial) data have also been collected regarding the occurrence of cognitive deficits (Behnisch 2021).

The diagnosis of iron deficiency anemia is made on the basis of history, clinical and laboratory findings (Herold 2022).

Since microcytosis and hypochromia only occur in severe iron deficiency anemia, the reduction of serum ferritin concentration (so-called storage protein for iron [Kaltwasser 2013]) is of decisive importance. False low values for serum ferritin have not been described so far (Kaltwasser 2013).

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

The determination of the iron concentration, on the other hand, is not diagnostically helpful (Burdach 2007). Iron concentration can indicate falsely low values in e.g. chronic inflammation and tumor disease and falsely high values in e.g. acute hepatitis (Kaltwasser 2013).

In addition, the cause of IDA must be clarified:

- clarification of bleeding 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)

- large blood count

- ferritin

- soluble transferrin receptor (sTfR)

- Zinc protoporphyrin (ZPP)

- Reticulocyte hemoglobin (Ret-Hb)

- Transferrin saturation (TSAT)

- Determination of hepcidin in urine:

In patients with hereditary iron refractory iron deficiency syndrome (IRIDA), normal to markedly elevated values are found, whereas in patients with alimentary iron deficiency it is severely decreased or absent (Behnisch 2021).

Laboratory chemistry can differentiate between different stages of iron deficiency anemia:

• Stage of storage iron deficiency:

This stage is also called "latent iron deficiency". In this case there are

- no anemia

- MCH and MCV are normal

- serum ferritin is decreased (however, increased values are found with simultaneous CRP increase)

- a reduced iron content can be found in the bone marrow (Herold 2022).

- Reticulocytes are decreased, the reticulocyte index is < 2 - 2.5.

- so-called hypoproliferative anemia (Kasper 2015).

• Stage 1:

In this case, a so-called "manifest iron deficiency" is already found.

In addition to the above symptoms, there is a

- reduction of the transferrin saturation (TSAT < 20 %) (Herold 2022).

• Stage 2:

Stage 2 of manifest iron deficiency - also referred to as "iron-deficient erythropoiesis" (Herold 2022).

It is characterized by additional

- Increase in soluble transferrin receptor (sTfR).

- Sideroblasts in the bone marrow decrease to < 15%.

- the percentage of hypochromic erythrocytes increases to > 10 % in flow cytometry

- Zinc protoporphyrin (ZPP) increases: This is an alternative metabolic pathway. Because of the lack of iron, zinc is incorporated and zinc protoporphyrin (ZPP) is formed instead of heme. This phenomenon is not specific to iron deficiency anemia, as it is also found in lead poisoning, iron utilization disorders, and myelodysplastic syndromes (MDS).

- Reticulocyte hemoglobin (Ret- Hb) decreases to < 26 pg (Herold 2022).

• Stage 3:

This stage is also known as "iron deficiency anemia". In this case, the following additional changes occur:

- Erythrocytes decreased

- Hemoglobin decreased (first sign, because hemoglobin production is disturbed earlier and more severely than erythropoiesis)

- hematocrit decreased

- reactive thrombocytosis due to cytostimulation

- Anisocytosis (irregularly sized erythrocytes) and consequent increase in RDW (red cell distribution width)

- Poikilocytosis (irregularly shaped erythrocytes)

- microcytic erythrocytes with an MCV < 80 fl

- hypochromic erythrocytes with an MCH < 28 pg (Herold 2022)

• Hypochromic anemia:

In this case, an MCH < 28 pg is found (Herold 2022).

• Runner's anemia:

This is a so-called dilutional anemia due to a large increase in plasma volume (Herold 2022).

• Gestational hydremia:

This is also a dilution anemia. It occurs here by an increase in total hemoglobin mass with a simultaneous increase in blood volume. In pregnant women, the term anemia is used only when the Hb < 11 g / dl (Herold 2022).

Differential diagnosis of hypochromic microcytic anemia:

• Thalassemia: In this case we find
  • normal or elevated iron levels
  • normal transferrin saturation (Kasper 2015)
  • Red blood cell distribution width (RDW) is normal - in contrast to iron deficiency anemia
• anemia due to chronic inflammation (most important differential diagnosis [Metzgeroth 2015])
  • ferritin normal or elevated
  • Percentage transferrin saturation below the normal value
  • TIBC decreased (Kasper 2015).
• myelodysplastic syndromes:
  • In these patients, there is often impaired hemoglobin synthesis with mitochondrial dysfunction. This leads to impaired iron incorporation into heme. Despite microcytosis and hypochromia, the iron values show normal stores and a more than adequate supply to the bone marrow (Kasper 2015).

With regard to the cause of iron deficiency anemia, appropriate causal therapy should be given, as well as appropriate iron supplementation (Herold 2022).

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

Iron substitution can take place as:

- oral iron therapy

- parenteral iron therapy

- erythrocyte transfusion (Kasper 2015)

- Erythropoiesis-stimulating agents (Metzgeroth 2015).

For more details see below "Internal therapy".

• Oral iron substitution

Iron substitution should be administered orally as initial therapy (Herold 2022). This includes in particular patients with proven iron deficiency anemia who are asymptomatic to date (Kasper 2015). Only bivalent iron should be used for oral therapy, as the intestine can only absorb 10-20% of this (Herold 2022).

Iron administration results in a two- to threefold production of red blood cells in patients with normal functioning bone marrow due to the corresponding erythropoietin- stimulus (Kasper 2015).

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 also better absorption due to the decrease in hepcidin (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 substitution

The indication for parenteral iron substitution is in patients who cannot tolerate oral iron, whose need is quite acute, or who require iron continuously. In recent years, parenteral administration has increased significantly (Kasper 2015).

Iron from dextran-free high molecular weight stable complexes should be used in this case. 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 proven 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).

• Red cell concentrates

Red blood cell transfusions are appropriate for patients with:

- cardiovascular instability

- severe iron deficiency anemia (Kasper 2015).

Here, the treatment is not so much related to the iron deficiency, but rather to the consequences of the severe anemia (Kasper 2015).

• Erythropoiesis-stimulating agents (ESA).

ESA increases the utilization of iron stores.

The administration of ESA has been shown to be particularly effective in patients with chronic renal insufficiency. However, it should be used only after functional and absolute iron deficiency have been corrected and the administration of ESA has been weighed against an increased risk of stroke (Elstrott 2020).

Deaths attributable to IDA are approximately 841,000 per year worldwide (Kasper 2015).

In particular, patients with chronic renal failure have an increased risk of morbidity (e.g., worsening heart failure) and also an increased risk of mortality in the presence of iron deficiency anemia (Gafter- Gvili 2019).

In patients with chronic heart failure alone, there is a 40%-60% increased risk of mortality in the presence of IDA (Elstrott 2020).

• 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

- can also lead to blackening of the tongue when dissolved

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

- may be toxic to children and 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).

• Prophylaxis

During pregnancy, preterm infants and neonates with a birth weight < 2,500 g should receive prophylactic iron supplementation (Herold 2022).

Pregnant women should be substituted from an Hb of 11 g / dl (10.5 g / dl) in the 1st trimester and from an Hb of 10.5 g / dl in the 2nd and 3rd trimesters up to an Hb- value of 12.0 g / dl (according to WHO).

(Means 2020)

Dosage recommendations:

- Pregnant women: 80 - 100 mg / d orally (Means 2020).

- In newborns < 2,500 g from the 8th week of life 2 - 2.5 mg / kg bw / d until the 12th - 15th month of life (Behnisch 2021).

1. Behnisch W, Muckenthaler M, Kulozik A (2021) AWMF guideline: Iron deficiency anemia. Registration number 025 - 021
2. 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
3. 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.
4. Gafter- Gvili A, Schechter A, Rozen- Zvi B (2019) Iron deficiency anemia in chronic kidney disease. Acta Haematol. 142 (1) 44 - 50
5. Herold G et al (2022) Internal Medicine. Herold Publishers 33 - 38
6. Kaltwasser J P, Werner E (2013) Serum ferritin: methodological and clinical aspects. Springer Verlag Berlin / Heidelberg / New York 2, 88.
7. Kasper D L et al (2015) Harrison's Principles of Internal Medicine. Mc Graw Hill Education, 625 - 629
8. Kühne T, Schifferli A (2016) Compendium of pediatric hematology. Springer Verlag Berlin / Heidelberg 13 - 19
9. Means R T (2020) Iron Deficiency and Iron Deficiency Anemia: Implications and Impact in Pregnancy, Fetal Development, and Early Childhood Parameters. Nutrients 12 (2) 447
10. Metzgeroth G, Hastka J (2015) Iron deficiency anemia and anemia of chronic diseases. The Internist (56) 978 - 988
11. Schwabe U, Paffrath T (2016) Drug prescription report 2016: current data, costs, trends and comments. Springer Verlag Berlin / Heidelberg 268
12. Tischendorf J W, Lutz H H (2019) New diagnostic tool for unclear iron deficiency anemia. Gastro- News (6) 11 - 12