Inflammatory anaemia D64.9

Anemia of inflammation (ACD = anemia of chronic disease) or also (AI = anemia of chronic inflammation) is an anemia with decreased serum iron levels (< 60 µg / dl) without decreased iron stores (Fränkel 2017).

Serum ferritin is NOT decreased (Nemeth 2014).

Inflammatory anemia is one of the hypoproliferative anemias along with:

- Iron deficiency anemia

- renal anemia

- endocrine anemia

- nutritional anemia

- anemia caused by bone marrow damage (Kasper 2015).

ACD can occur in acute and as well as chronic inflammation (Fränkel 2017).

Normally, it is a normochromic normocytic anemia (Nemeth 2014), but it can become microcytic as it progresses (Cullis 2013). Only in 25% a slightly hypochromic ACD is found (Herold 2022).

ACD is one of the most common forms of anemia (Kasper 2015).

Patients with stage I and II chronic kidney disease show inflammatory anemia in < 10% (with an Hb < 12 g / dl in women and an < 13 g / dl in men), in stage III in 20-40%, in stage IV between 50-60%, in stage V in > 70% and in stage dialysis in up to 90%. However, the prevalence of severe anemia with an Hb ≤ 10 g / dl is much rarer (Gluba- Brzozka 2020).

Fränkel (2017) describes a study of hospitalized elderly patients in whom inflammation-related anemia was present in 70%. In patients with carcinomas, anemia was found in 63.4%.

Patients with malignant tumors have anemia with Hb- values between7 - 11 g / dl. Of these, 18 - 34 % require transfusions (Link 2006).

- acute and chronic infections

- advanced malignant disease (Fränkel 2017)

- autoimmunological diseases (Kaltwasser 2009)

An older age and renal failure have an unfavorable effect (Fränkel 2017).

The polypeptide hepcidin, which is primarily formed in the liver and excreted via the kidneys (Nemeth 2014), inhibits the ability of the intestine to absorb iron. In chronic inflammation, it is increased by inflammatory toxins, especially interleukin. In addition, iron absorption by duodenal enterocytes is downregulated. Thus, a state of functional iron deficiency develops (Cullis 2013).

Erythropoietin (EPO) produced in the kidney promotes the formation of erythrocytes. In inflammatory anemia, the increase in EPO that normally follows a drop in Hb- levels is attenuated (Cullis 2013).

In chronic inflammation, endogenous EPO- production is too low because the bone marrow responds inadequately to stimulation (Kasper 2015).

Fränkel (2017) points to recent studies showing that ACD can be caused by both impaired erythropoiesis and iron sequestration. Proinflammatory cytokines released by inflammation suppress erythropoiesis and cause iron sequestration by the hormone hepcidin. In addition, changes in the cell membrane shorten erythrocyte survival.

In summary, the following factors play a role in ACD:

- 1. slightly shortened erythrocyte survival due to destruction of the cell wall.

- 2. occurrence of hypoferremia due to limited uptake of iron during erythropoiesis due to cytokine stimulation of hepcidin.

- 3. suppression of erythropoiesis by direct action of cytokines on bone marrow.

- 4. effects of inflammation on erythropoietin production are variable (Nemeth 2014).

- Decrease in hemoglobin levels:

Fever and cytokines released during infection exert selective pressure on the erythrocyte membrane, resulting in rupture of the membrane (Kasper 2015).

- Chronic renal failure:

Anemia occurring in chronic renal failure represents a multifactorial process:

- deficient production of erythropoietin in the peritubular cells of the kidneys

- resulting defective erythropoiesis

- impairment of iron utilization

- stimulation of hepcidin production

- Loss of iron through hemodialysis (on average 1 - 3 g / year)

- Occurrence of hyperparathyroidism

- Deficiency of essential nutrients such as folic acid, iron, vit. B

- uremic toxins

- Medications such as ACE inhibitors

- V. a. a peripheral resistance to EPO (Gluba- Brzozka 2020)

- Positive effects of anemia:

Decreased available iron blocks the growth of invading pathogens. In addition, the deprivation of iron leads to a strengthening of the immune defense mechanisms of macrophages (Weiss 2009).

Symptoms are primarily determined by the underlying disease (Bob 2001).

The diagnosis is made on the basis of laboratory chemical changes: hypoferremia, low (to normal [Endres 2022]) transferrin saturation, presence of Prussian blue stained iron in bone marrow macrophages (Nemeth 2014).

- Mild to moderate anemia (Hb only rarely < 8 g / dl (Nemeth 2014).

- Decrease of the hemoglobin value

This can drop by 2 - 3 g / dl within 1 - 2 days due to hemolysis of erythrocytes in acute infection (Kasper 2015).

- Serum iron decreased (< 50 µg / dl [Kasper 2015]).

- Transferrin increased

- absent storage iron in the bone marrow (Herold 2022)

- sTfR normal (Cullis 2013) or decreased (Endres 2022).

- Serum ferritin normal [Nemeth 2014] (30 - 200 µg / dl) (Kasper 2015) to increased (Endres 2022)

- MCV normal to decreased

- MCH normal (Cullis 2013)

- total iron binding capacity < 300 µg / dl

- ferritin in serum increased up to 3-fold

- peripheral blood smear occasionally shows polychromatophilic reticulocytes

- erythrocyte protoporphyrin concentration > 1.2 µM

- transferrin saturation > 15

- extremely low erythropoietin levels

- elevated inflammatory markers due to the underlying disease (Fränkel 2017)

- Reticulocytes normal (Endres 2022)

- Iron Deficiency Anemia

No Prussian blue stained iron can be detected in bone marrow macrophages in iron deficiency anemia. However, this test has since been replaced by serum ferritin determination, as a decreased serum ferritin value is highly specific for iron deficiency anemia (Nemeth 2014).

Further differentiation is possible by determining the serum transferrin receptor (sTfR), which rises in iron deficiency anemia and remains slightly lower or unchanged in ACD (Cullis 2013).

It is not uncommon for chronic inflammation to be accompanied by chronic blood loss. In this case, iron deficiency anemia occurs in addition to ACD. Differential diagnoses include bone marrow aspirate stained for iron (Kasper 2015).

See also "Differential diagnoses".

The best treatment option is therapy of the underlying condition, as this usually also leads to an improvement in the anemia (Cullis 2013). Blood transfusions, agents that stimulate erythropoiesis such as epoetin [Cullis 2013]), intravenous iron therapy (Fränkel 2017), and vitamin D treatment (Icardi 2013) are also helpful.

Blood transfusions: Blood transfusions are indicated for life-threatening degrees of anemia with an Hb< 6.5 g / dl and likewise before surgical procedures in patients with ACD (Kaltwasser 2009).

Erythropoietin: Drugs such as darbepoetin, epoetin alpha and epoetin beta are available here. With these drugs, there is a 100% therapeutic success, provided that iron is simultaneously substituted in the case of a functional iron deficiency (recognizable by an adequate storage iron in combination with the increase of hypochromic erythrocytes in the peripheral blood) (Kaltwasser 2009).

Dosage recommendations:

- Epoetin alpha: 150 IU / kg bw s. c. 3 x weekly. If this does not achieve therapeutic success (increase in Hb- value after 4 weeks by ≥ 1 G / dl [Demetri 2001]), the dose should be increased to 300 IU / kg bw s. c. 3x weekly. If the patient does not respond even to doubling the dose, therapy should be discontinued (Demetri 2001).

- Epoetin beta: 450 IU / kg bw s. c. every 7 days.

- Darbepoetin: 2.25 µg / kg bw s. c. every 7 days (Manski 2020).

Iron substitution: Iron substitution should be given to ACD- patients with completely depleted iron stores (Kaltwasser 2009).

In addition, iron therapy may be necessary if functional iron deficiency occurs during the course of treatment with erythropoietin. In this context, this is recognizable by sufficient storage iron in combination with an increase in hypochromic erythrocytes in the peripheral blood.

Therapy should be parenteral, as this is superior to oral administration in terms of effectiveness (Kaltwasser 2009).

Vitamin D: Administration of native or analog vitamin D improved anemia and reduced the need for erythropoiesis-stimulating agents in studies by Icardi (2013) in patients with chronic renal failure.

According to Cooper's 2012 CRIT study, severe anemia (Hb < 9 g / dl) in the setting of inflammation is a predictor of increased mortality (Cooper 2012).

In patients with chronic kidney disease , morbidity and mortality are generally increased in the setting of ACD (Gluba- Brzozka 2020).

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