Iron substitution

Iron substitution is the administration of iron in the form of drugs, transfusions, or EPO (Metzgeroth 2015) in cases of laboratory-proven iron deficiency or for prophylaxis of iron deficiency (Herold 2022).

The substitution of iron can be done:

• by drugs
  • orally
  • parenterally
• by erythrocyte transfusion (Kasper 2015)
• by erythropoiesis-stimulating agents (Metzgeroth 2015)

• 1. oral iron therapy

Only divalent iron should be used for oral treatment, as the intestine can only absorb this and only 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 ++, while trivalent iron ions from plant foods must first be reduced to divalent ions in the apical cell membrane (Behnisch 2021).

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

Indications:

- Patients with proven iron deficiency anemia, even with previously asymptomatic course (Kasper 2015).

- Patients with symptomatic iron deficiency anemia (Herold 2022).

- Pregnancy:

- Premature infants

- Neonates with a birth weight < 2,500 g (Herold 2022).

- Restless Leg Syndrome (RLS)

(Elstrott 2020)

Dosage recommendation:

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

- In pregnant women: 80 - 100 mg / d orally (Means 2020). Pregnant women are to be substituted in the 1st trimester from an Hb of 11 g / dl (10.5 g / dl) 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)

- 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).

- Premature infants should receive 2 - 3 mg / kg / bw / d, but not more than 5 mg / kg / bw / d from the 3rd - 4th week of life for 6 - 12 months (Ehlen 2014).

- Restless Leg Syndrome:

Patients with RLS benefit from 6 weeks of treatment with iron if serum ferritin ≤ 75 µg / l (Elstrott 2020).

Adverse effects:

- Gastrointestinal symptoms 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 one week (Herold 2022), if the iron deficiency is severe. Serum ferritin should be checked after about 3 months (Behnisch 2021).

Preparations:

- Iron II- Sulfate Tablets

- Iron II- Furamate tablets (Wick 2013)

- Ferrosanol drops (Ehlen 2014)

• 2. parenteral iron therapy

Trivalent 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).

Indication:

S. a. Iron, intravenous

The indication for parenteral iron substitution is given 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 the presence of iron deficiency can alleviate symptoms even in the absence of iron deficiency anemia (Lundgren 2018).

- Z. n. bariatric surgery (Elstrott 2020).

- Acute mountain sickness (AMS):

This occurs in approximately 50% of people who travel to high altitudes. The incidence can be reduced by prophylactic iron therapy, as iron supplementation reduces the hypoxia-inducing factor (HIF) involved in the development of AMS (Elstrott 2020).

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

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).

Side effects:

Parenteral substitution carries a risk of severe allergic reactions. Although the risk of anaphylaxis is lower with modern iron preparations, in addition, high-molecular-weight dextran preparations are now no longer commercially available in Germany (Kuhlmann 2015).

Side effects include:

- Severe allergic reactions

- occur with iron dextran in 33 cases per 10 million applications

- iron gluconate in 9 cases per 10 million applications

- 6 cases per 10 million applications of iron sucrose (Kuhlmann 2015).

- Paravalvular injection with

- severe pain at the injection site (Hitchings 2022)

- phlebitis

- persistent brown discoloration of the skin (Hitchings 2022)

- headache

- nausea

- vomiting

- metallic taste

- cardiac pain

- danger of overdose

- thrombophlebitis (Herold 2022)

Patients with an atopic disposition should not receive parenteral iron because they are at significantly increased risk of serious complications (Hitchings 2022)

In October 2013, because of severe anaphylactic reactions, the German Medical Association and the European Supervisory Authority issued a warning for intravenous iron administration, stating:

- The indication for intravenous therapy is only given after unsuccessful oral treatment

- Possible risk groups are to be identified before starting therapy

- A detailed explanation is necessary before the first treatment and should be repeated at regular intervals.

- The first injection must be given under the direct supervision of a physician.

- Personnel experienced in resuscitation must be in the immediate vicinity

- The recommended infusion duration of 15 - 30 min must be strictly observed

- After the infusion, follow-up monitoring is required. This is 60 min for the first administration and ≥ 30 min for subsequent infusions (Kuhlmann 2015)

However, side effects are found relatively rarely in hemodialysis patients (Kuhlmann 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).

For more details, see Iron, intravenous.

• 3. erythrocyte transfusion

When treating iron deficiency with red blood cell transfusion, it is less important to correct the iron deficiency than to correct the consequences of severe anemia (Kasper 2015).

Indication:

- Risk of anemic hypoxia (Hönemann 2020).

- persistent or excessive blood loss

- cardiovascular instability (Kasper 2015).

• 4. 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).

Indication:

- Chronic kidney disease:

- Symptomatic anemia despite compensation of iron deficiency.

- Hb < 9 g / dl (< 5.6 mmol / l)

- To avoid the need for transfusion (Schwenger 2021).

- Oncology:

- Somatic chemotherapy-induced anemia with an Hb ≤ 10 g / dl (6.2 mmol / l) (Serve 2021)

Dosage recommendation

Substitutes are usually recombinant erythropoietin or EPO derivatives such as darbepoetin or Cera.

- EPO 1 - 3 x weekly

- Darbepoetin 1 x weekly

- Cera 1 x every 4 weeks (Schwenger 2021)

Duration

It should be substituted up to a Hb- value of 11.5 g / dl (7.1 mmol / l) (Weihrauch 2020).

Side effects

- erythema at the injection site

- thromboembolic events (Rieger 2022)

Preparations

EPO derivatives such as darbepoetin, Cera (Schwenger 2021).

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

- 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).

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