Inflammatory anemia

Causes and Mechanisms of Chronic Disease Anemia

Researchers finally established the definition of anemia caused by chronic diseases around 1960 when they conducted several larger-scale infection-related studies. Many authors agree that infections and inflammation, including immune connective tissue diseases and neoplasms, account for the main causes of these anemias in 75% of cases. Diagnosing these conditions is not always easy, and one should suspect them when encountering anemia.

The causes of these anemias can be long-lasting infectious diseases such as infective endocarditis, chronic heart failure, chronic kidney diseases (especially in dialysis patients), osteomyelitis, hepatitis B and C, and AIDS. Intestinal diseases like Crohn's disease and nonspecific ulcerative colitis can also cause inflammatory anemia. In oncology, the most severe inflammatory anemias occur in patients with Hodgkin's disease, lymphoma, and those undergoing chemotherapy. Doctors often diagnose anemia in patients with liver cirrhosis.

Immune mechanisms cause anemia in chronic diseases: cytokines released by reticuloendothelial cells and lymphocytes lead to changes in iron metabolism, the proliferation and differentiation of erythroid precursors, erythropoietin production, and the lifespan of red blood cells. For this reason, experts also refer to anemia in chronic diseases as inflammation anemia.

Types and Diagnosis of Chronic Disease Anemia

Inflammatory anemia is usually mild to moderate (hemoglobin (Hgb) is rarely less than 80 mg/l). Biochemical tests help recognize this type of anemia by identifying low iron concentration in the blood serum despite adequate iron reserves in the body. The concentration of transferrin in the blood serum also reduces, but this appears as a late sign due to transferrin's longer half-life (about 8 days) compared to iron (about 1.5 hours). Red blood cells typically maintain normal size and hemoglobin (Hgb) concentration, albeit with a reduced count in the blood, which describes normocytic normochromic anemia. In some cases, especially in prolonged inflammatory diseases, red blood cells may decrease, leading to a decrease in Hgb.

Anemia of critical illness presents similar symptoms, but in patients with infection, sepsis, or other inflammatory diseases treated in intensive care units, it develops over a few days. In such cases, anemia is exacerbated by frequent diagnostic phlebotomies or increased gastrointestinal blood loss.

Senile anemia is a chronic condition similar to inflammatory anemia but occurs in aging individuals without specific predisposing diseases. The prevalence increases with age, and detailed studies often indicate an increase in C-reactive protein (CRP) or other inflammatory biomarkers.

Experts often attribute anemia of chronic kidney diseases to erythropoietin deficiency anemia. However, studies show that the pathogenesis of anemia in chronic kidney disease is much more complex and only partially involves components of inflammatory anemia. For example, renal anemia develops in chronic kidney failure when the creatinine concentration in the blood surpasses a certain threshold, indicating impaired kidney function and reduced erythropoietin production.

Diagnostic challenges

The diagnosis of anemia of inflammatory diseases is made by assessing clinical signs and laboratory parameters. Since anemia of chronic diseases progresses slowly and, according to literature data, is not usually very severe, clinical symptoms are often minimal and vague. Clinical signs reflect the underlying disease (infection, inflammation, oncological disease, chronic kidney or heart failure), overshadowing the symptoms of anemia. Clinical symptoms of anemia are related to tissue hypoxia. Weakness, syncope, irritability, headache, pallor, dyspnea, and chest pain are most commonly observed. In more severe cases, thirst, tachycardia, orthostatic hypotension, and tachypnea may occur. Sometimes hepatomegaly and/or splenomegaly are diagnosed, and during neurological examination, symptoms of peripheral neuropathy are observed.

Laboratory diagnosis of anemia caused by chronic diseases is performed by excluding other causes of anemia, as there are no specific laboratory parameters specific to this pathology. Tests include Hgb concentration, erythrocyte and reticulocyte counts, hematocrit, iron and ferritin concentration in the blood serum, and transferrin saturation. Patients with this type of anemia have low Hgb levels, decreased or normal reticulocyte count, decreased iron levels, while ferritin concentration is normal or increased. This reflects increased iron accumulation and retention in the reticuloendothelial system, as ferritin is a marker of iron reserves.

Traditional and Modern Diagnostic Approaches

Traditionally, the gold standard for diagnosing inflammatory anemia was the finding of decreased iron concentration in the blood (hypoferrimia) or low transferrin saturation despite the presence of Prussian blue stain (iron-stained) in bone marrow macrophages identified by a myelogram. Critics have pointed out problems with this gold standard, not only due to the invasive technique of bone marrow sample collection but also because different interpretations often arise from these samples. Researchers found that iron therapy can lead to questionable quality iron deposition in bone marrow, which may later be inadequately utilized in patients' bodies lacking it. As a result, healthcare providers have replaced this method with the determination of serum ferritin concentration as the determinant.

Serum Ferritin as a Modern Diagnostic Tool

A low ferritin concentration in blood serum (less than 15ng/ml in the general population; some laboratories use age- and gender-specific norms) is a highly specific sign of iron deficiency (genetic L-ferritin deficiency is a rare exception) and effectively rules out inflammatory anemia, indicating that there are no iron reserves in the body. The latter is diagnosed when anemia and hypoferrimia occur without low ferritin concentration in serum. Ferritin concentration increases in the presence of inflammation. It is important to mention that ferritin originates from macrophages, where its synthesis increases due to iron sequestration processes in the background of inflammation. It is believed that iron deficiency coexists with anemia of chronic diseases when ferritin does not increase sufficiently due to the intensity of inflammation. Serum ferritin also increases due to tissue damage, especially in cases of liver injury.

Challenges with Modern Diagnostic Methods

A very low ferritin determinant in clinical practice can be difficult to detect because patients with high ferritin concentration in blood serum may respond positively to intravenous iron therapy—their Hgb concentration also increases. Essentially, researchers could identify the limit of serum ferritin by examining additional signs of iron deficiency that inflammation less affects, such as the most prominent soluble transferrin receptors. However, it is important to note that these respective studies are not standardized and their evidence remains questionable. When doctors detect clinically significant anemia and suspect iron deficiency in patients with chronic disease anemia, they may justify treatment with intravenous iron as a therapeutic method. Modern preparation for intravenous iron therapy is quite safe, but when considering its application, a risk-benefit analysis should include very rare reactions and the possibility of exacerbating an existing or hidden infectious process.

Prevalence

There is no detailed statistics on the prevalence of inflammatory disease anemia. Estimates suggest that the aging population and the high frequency of chronic infections and inflammatory disorders worldwide place inflammatory disease anemia second in the list of anemia types, after iron-deficiency anemia. However, the situation may change as iron deficiency anemia becomes more effectively treated.
For example, the prevalence of anemia varies approximately from 10% in patients with moderate chronic heart failure (CHF) to over 50% in patients with severe CHF. Reduced Hgb concentration in patients with CHF is harmful as it further reduces tissue oxygen supply, increases systolic volume, intensifies cardiac work. This can lead to exhaustion and result in an increase in left ventricular mass and dilation, myocardial ischemia, and progression of heart failure symptoms.

Pathophysiology

Key Pathophysiological Principles

• Slightly shortened red blood cell survival (increased destruction).
• Hypoferrimia, cytokine-stimulated hepcidin increase, and iron-blocking erythropoiesis.
• Suppression of erythropoiesis due to the direct effect of bone marrow cytokines.
• Various inflammatory effects on erythropoietin production and renal hepcidin secretion.

Mechanisms of Chronic Disease Anemia

A prolonged inflammatory process causes chronic disease anemia, during which activated reticuloendothelial cells and released cytokines disrupt iron homeostasis. These disruptions induce the proliferation of erythroid progenitor cells, worsen erythropoietin production, shorten the lifespan of red blood cells, and ultimately reduce hemoglobin (Hgb) production.

Erythropoiesis can be disrupted in several ways, including during infections (such as hepatitis C, malaria, HIV) or infiltration of bone marrow by tumor cells. Tumor cells stimulate the production of inflammatory cytokines and free radicals, which damage erythroid progenitor cells. Additionally, health is further compromised by episodes of bleeding, vitamin deficiencies (cobalamin, folic acid), hypersplenism, autoimmune hemolysis, renal insufficiency, radiotherapy, and chemotherapy.

In anemia caused by chronic diseases, cytokines secreted by reticuloendothelial cells disrupt iron metabolism, resulting in increased iron absorption and accumulation in reticuloendothelial cells. Cytokines stimulate the immune system to use more iron, causing immune cells to break down red blood cells and absorb their iron content. During this process, the structure of immune cells changes, making it harder for them to release iron. The iron accumulates in macrophages, does not enter the bone marrow, and is not used for Hgb synthesis, leading to iron deficiency erythropoiesis.

The Role of Hepcidin and Erythropoietin in Inflammatory Anemia

Another inflammatory product, hepcidin, produced in the liver, inhibits iron absorption from the intestine. As hepcidin levels increase, less Hgb is produced. During inflammation, cytokines decrease erythropoietin production or provoke a poor response to this hormone. This deterioration is associated not only with the pro-inflammatory cytokine effect on proliferating erythroid precursors but also with the inhibition of the erythropoietin receptors' function on these cells. Erythropoietin initiates an increase in the production of erythrocytes and Hgb and regulates the proliferation of erythroid cells. The weakening of erythropoietin function causes anemia. A separate type of this anemia is associated with chronic kidney diseases and kidney failure when there is a deficit of erythropoietin. The antiproliferative effect of uremic toxins is also important for the pathogenesis of anemia. In hemodialyzed patients, erythropoietin deficiency can develop if the hormone is removed more during dialysis.

Oncological Diseases and Anemia

As mentioned, one of the most common causes of chronic anemia is oncological diseases. Reduced iron metabolism and suppressed erythropoiesis are the first signs of cancer-related anemia. In the presence of a malignant tumor, the lifespan of red blood cells decreases. The bone marrow cannot increase erythropoiesis or release iron from aging red blood cells that bone marrow macrophages have phagocytosed, leading to an iron reutilization defect. The hypoproliferative state of tumor-related anemia results from decreased erythropoietin production or a deteriorated bone marrow response to the hormone. Inadequate erythropoietin production associates with increased production of tumor cytokines.

Several cytokines (TNF-alpha, IL-1, IL-6, interferon-gamma, transforming growth factor beta, and EPO) are responsible for the inhibition of erythropoiesis and the weakening of iron metabolism. In vitro studies have shown that tumor necrosis factor (TNF-alpha) and interleukin-1 (IL-1) inhibit mRNA synthesis, indicating that the hypoproliferative response may be an indirect sign of cytokine activity. Thus, anemia in patients with oncological diseases can be characterized as a cytokine-related syndrome in which various cytokines interact, causing inhibition of erythropoiesis and disrupting iron metabolism.

Therapeutic Measures and Considerations

Blood component transfusion is widely used as a quick and effective therapeutic measure. Red blood cell transfusions are very useful in treating severe anemia. However, iron therapy for anemia associated with chronic diseases is debatable. Iron-saturated macrophages cannot phagocytize microorganisms and altered cells. Additionally, iron therapy, in the presence of long-term immune activation, promotes the formation of highly toxic hydroxyl radicals, which can cause tissue damage, endothelial dysfunction, and increase the risk of serious cardiovascular events.

On the other hand, iron therapy can also be beneficial. Treatment with iron preparations suppresses the formation of TNF-alpha and reduces disease activity in rheumatoid arthritis or end-stage kidney disease. Besides iron deficiency, functional iron deficiency develops in patients with anemia caused by chronic diseases, as intensive erythropoiesis occurs during treatment with erythropoietic drugs. In patients undergoing chemotherapy or hemodialysis, parenteral iron improves the response to treatment with erythropoietic drugs.

Healthcare providers approve erythropoietic drugs for treating inflammatory anemia in patients with oncological diseases undergoing chemotherapy, chronic kidney disease, HIV infection, or those treated with myelosuppressive drugs. When treating chronic disease-related anemia with erythropoietin, they observe a good response in 25% of patients with myelodysplastic syndrome, 80% with multiple myeloma, and up to 95% with rheumatoid arthritis or chronic kidney disease. Increased levels of pro-inflammatory cytokines and poor iron transfer from macrophages are associated with a poor response to treatment with erythropoietic drugs.

The main treatment methods are as follows:

• Treat the underlying disease.
• Administer specific treatments for severe anemia or disturbances in daily activity.
• Use erythropoiesis-stimulating factors with or without intravenous iron therapy (not yet approved).
• Consider experimental therapies, including new erythropoiesis-stimulating agents (such as epoetin alfa and darbepoetin alfa), anti-cytokine drugs, and agents affecting the hepcidin-ferroportin mechanism.

Researchers widely describe a new treatment method using pentoxifylline, which is not a new drug. Clinical studies evaluating the effect of pentoxifylline on patients with chronic diseases have revealed a previously unnoticed property: pentoxifylline not only improves blood flow, reduces blood viscosity, platelet adhesion, and aggregation but also increases hemoglobin (Hgb) concentration. Effective correction of anemia increases the survival of patients with chronic diseases and improves disease outcomes. In patients with chronic heart failure, it also improves heart function. Therefore, pentoxifylline can help achieve better results.

Pentoxifylline is a derivative of methylxanthines that improves blood flow and inhibits platelet function, thereby improving tissue blood circulation, oxygen, and nutrient supply. Oxygenation is significantly improved where ischemia is more severe. The favorable effect of pentoxifylline on blood rheological properties is due to the reduction in whole blood and plasma viscosity caused by intensified fibrinolysis or decreased fibrinogen synthesis (resulting in decreased fibrinogen concentration). These processes are influenced by the increased concentration of adenosine triphosphate, cyclic adenosine monophosphate, and other cyclic nucleotides in erythrocytes.

In recent years, it has been discovered that pentoxifylline not only reduces blood viscosity and improves blood circulation but also affects the immune response of the body. This finding has received significant attention. It has been found that pentoxifylline blocks TNF-alpha, which stimulates the adhesion of neutrophils to vessel walls. Thrombi form in altered blood vessels, leading to vessel narrowing and impaired tissue blood flow. Therefore, this anti-inflammatory effect of pentoxifylline is also important.

Thus, pentoxifylline:

- Increases the ability of red blood cells to deform;
- Inhibits platelet aggregation;
- Stimulates prostacyclin synthesis, thereby inhibiting platelet aggregation;
- Reduces elevated fibrinogen concentration;
- Reduces increased blood viscosity;
- Inhibits leukocyte adhesion to the endothelium;
- Suppresses leukocyte activation and the endothelial damage it causes;
- Moderately dilates blood vessels.

The indications for the use of pentoxifylline as a microcirculation regulator have been identified as:
- Atherosclerotic, diabetic, inflammatory, or functional peripheral arterial or arterial and venous circulation disorders;
- Intermittent claudication or pain at rest, diabetic angiopathy, obliterative endangiitis;
- Trophic disorders (post-thrombotic syndrome, leg ulcers, gangrene);
- Angioneuropathies;
- Acute and chronic retinal and choroidal circulation disorders;
- Insufficient cerebral blood flow (ischemic and post-stroke conditions);
- Vascular origin disorders of inner ear function (impaired hearing, sudden hearing loss, etc.).

Pentoxifylline is contraindicated after recent myocardial infarction, episodes of severe bleeding, extensive retinal bleeding, or in case of hypersensitivity to pentoxifylline or other methylxanthines.

Conclusions

- Anemia caused by chronic diseases is the second most common type of anemia. It usually develops due to immune system activation or bone marrow suppression.
- Chronic heart failure, chronic kidney failure, and oncological diseases are among the most common chronic diseases causing anemia.
- Inflammatory (chronic disease-related) anemia is caused by reduced iron levels in the blood due to hepcidin, cytokine-induced erythropoiesis suppression, and decreased red blood cell lifespan.
- Treatment with erythropoiesis-stimulating factors and/or intravenous iron is rarely needed.
- The positive effect of pentoxifylline on blood rheological properties has already been proven. The latest research data on pentoxifylline's ability to increase blood Hgb concentration provide new hope for effective treatment solutions for inflammatory anemia.

*Publication "Internistas" No.9, 2019.*

**Rūta Mačiulytė**
*Vilnius University Faculty of Medicine*

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