How to Diagnose and Manage Anemia of Chronic Disease in Clinical Practice

A Comprehensive Guide: Anemia of Chronic Disease – Diagnosis, Management, and Innovative Treatments

Anemia of chronic disease (ACD), also known as anemia of inflammation, is the second most common form of anemia worldwide, following iron-deficiency anemia. It is commonly associated with chronic infections, autoimmune diseases, and malignancies, and is considered a protective mechanism by the body to limit the availability of iron to pathogens or malignant cells. Despite its frequency, diagnosing and managing anemia of chronic disease can be challenging due to its multifactorial etiology and the complexities surrounding its treatment.

This guide provides a detailed exploration of anemia of chronic disease, covering its pathophysiology, clinical presentation, diagnosis, management, and recent advances in treatment. Written for medical students and doctors, this resource aims to deepen understanding and improve clinical approaches to this condition, helping practitioners deliver optimal care.

Understanding Anemia of Chronic Disease: Pathophysiology and Underlying Mechanisms

Anemia of chronic disease is characterized by impaired red blood cell (RBC) production, driven by chronic inflammation and a blunted erythropoietic response. Unlike other forms of anemia, ACD is not primarily due to a deficiency in iron or vitamins but rather due to dysregulation of iron homeostasis and impaired erythropoiesis. The following mechanisms contribute to the development of ACD:

1. Iron Sequestration and Dysregulation

In the presence of chronic inflammation, the liver produces increased amounts of hepcidin, a key regulatory hormone that controls iron homeostasis. Hepcidin inhibits the release of iron from macrophages and enterocytes by binding to and degrading ferroportin, the main iron transporter in cells. This results in iron being sequestered in macrophages and not available for erythropoiesis.

• Iron Trapping in Macrophages: Iron is trapped in macrophages and cannot be recycled for use in red blood cell production, even though total body iron stores may be normal or elevated.
• Reduced Iron Absorption: Hepcidin also decreases the absorption of dietary iron from the gastrointestinal tract, further limiting iron availability.

2. Blunted Erythropoietin Response

In chronic disease states, the body’s response to anemia via erythropoietin (EPO) production is dampened. While EPO levels may be inappropriately normal or only modestly elevated, the bone marrow’s response to EPO is also impaired. Inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) play key roles in suppressing erythropoiesis.

3. Shortened Red Blood Cell Lifespan

Chronic inflammation also leads to a reduction in the lifespan of circulating red blood cells, primarily through increased macrophage activity. This accelerated clearance of RBCs contributes to the development of mild to moderate anemia in chronic disease states.

Common Conditions Associated with Anemia of Chronic Disease

Anemia of chronic disease can occur in the setting of any long-term inflammatory condition. Some common examples include:

• Chronic infections: Tuberculosis, HIV, chronic osteomyelitis.
• Autoimmune diseases: Rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease.
• Chronic kidney disease (CKD): One of the most common causes of ACD, due to both reduced erythropoietin production and chronic inflammation.
• Malignancies: Particularly solid tumors and lymphoproliferative disorders.
• Heart failure and chronic liver disease.

Clinical Presentation of Anemia of Chronic Disease

The clinical manifestations of anemia of chronic disease are often subtle and masked by the underlying chronic illness. In many cases, the anemia is mild to moderate, and patients may not experience symptoms specifically due to the anemia. Instead, the symptoms of the underlying condition predominate.

Common Symptoms of ACD:

• Fatigue and Weakness: The most common symptoms due to reduced oxygen-carrying capacity.
• Pallor: Particularly noticeable in the skin and mucous membranes.
• Shortness of Breath on Exertion: Patients may develop dyspnea during physical activity due to decreased oxygen delivery to tissues.
• Dizziness or Lightheadedness: Caused by reduced oxygenation of the brain, especially during periods of exertion.
• Exacerbation of Underlying Chronic Disease Symptoms: In some cases, anemia can worsen the symptoms of the underlying chronic illness, such as heart failure or rheumatoid arthritis.

Unique Presentations Based on Underlying Disease:

• Rheumatoid Arthritis: Patients may experience worsening joint pain and fatigue due to anemia.
• Chronic Kidney Disease (CKD): Anemia is often more pronounced due to a combination of impaired erythropoietin production and inflammation.
• Cancer: Anemia of chronic disease in cancer patients may be associated with tumor-related factors, chemotherapy, or bone marrow suppression.

Diagnosis of Anemia of Chronic Disease

Diagnosing anemia of chronic disease requires a thorough clinical evaluation and laboratory investigations to differentiate it from other forms of anemia, particularly iron-deficiency anemia. ACD can present similarly to iron-deficiency anemia, but the underlying mechanisms differ, necessitating careful interpretation of lab results.

1. Complete Blood Count (CBC)

A CBC is the first step in diagnosing anemia of chronic disease. Typical findings include:

• Mild to Moderate Anemia: Hemoglobin levels are usually between 8-11 g/dL, though more severe cases can occur in chronic kidney disease or malignancy.
• Normocytic or Microcytic Anemia: Most cases present with normocytic (normal-sized RBCs) anemia, but some cases may present as microcytic (small RBCs) anemia, particularly in long-standing chronic diseases.

2. Iron Studies

Iron studies are crucial for differentiating anemia of chronic disease from iron-deficiency anemia:

• Serum Ferritin: In ACD, ferritin levels are typically normal to elevated, as ferritin is an acute-phase reactant. In contrast, iron-deficiency anemia usually shows low ferritin levels.
• Serum Iron: Low in both ACD and iron-deficiency anemia.
• Total Iron-Binding Capacity (TIBC): TIBC is typically low in ACD, reflecting the decreased need for iron transport due to sequestration in macrophages. In iron-deficiency anemia, TIBC is usually elevated.
• Transferrin Saturation: Reduced in both ACD and iron-deficiency anemia, but generally more pronounced in iron-deficiency anemia.

3. Erythropoietin (EPO) Levels

In anemia of chronic disease, erythropoietin levels may be inappropriately normal or only mildly elevated, reflecting the blunted response to anemia. This contrasts with conditions like iron-deficiency anemia, where EPO levels are typically elevated in response to low hemoglobin.

4. C-Reactive Protein (CRP) and Erythrocyte Sedimentation Rate (ESR)

Both CRP and ESR are elevated in chronic inflammatory conditions, reflecting the underlying inflammation that contributes to anemia. These markers help confirm the presence of an inflammatory process driving the anemia.

5. Bone Marrow Biopsy (Rarely Required)

In rare cases where the diagnosis is unclear, a bone marrow biopsy may be performed. Findings in anemia of chronic disease include normal or increased iron stores within macrophages, reflecting iron sequestration, and reduced erythropoiesis.

Management of Anemia of Chronic Disease

The management of anemia of chronic disease is primarily focused on treating the underlying chronic condition and improving the quality of life for patients. Since ACD is often a consequence of another disease, addressing the root cause is essential for effectively managing the anemia.

1. Treating the Underlying Cause

The cornerstone of managing anemia of chronic disease is controlling the underlying chronic condition. This may involve:

• Anti-inflammatory Therapy: For autoimmune conditions such as rheumatoid arthritis or inflammatory bowel disease, the use of anti-inflammatory agents (e.g., corticosteroids, disease-modifying antirheumatic drugs [DMARDs], or biologics) can help reduce inflammation and improve anemia.
• Infection Control: In patients with chronic infections such as tuberculosis or HIV, controlling the infection can lead to improvement in anemia.
• Cancer Treatment: In patients with malignancies, effective cancer treatment (e.g., chemotherapy, radiation, or surgery) may alleviate anemia by reducing tumor burden and inflammatory cytokine production.
• Chronic Kidney Disease Management: For patients with CKD, addressing the renal dysfunction with medications, dialysis, or transplant may improve anemia.

2. Erythropoiesis-Stimulating Agents (ESAs)

ESAs, such as erythropoietin (EPO) and darbepoetin alfa, are commonly used in patients with anemia of chronic disease, particularly those with chronic kidney disease, cancer, or other conditions associated with reduced erythropoietin production.

• Mechanism of Action: ESAs stimulate the bone marrow to increase red blood cell production.
• Indications: Primarily used in patients with chronic kidney disease or cancer-associated anemia, where erythropoietin production is insufficient.
• Dosing and Monitoring: ESA therapy requires careful monitoring to avoid complications such as hypertension, thromboembolic events, and overcorrection of anemia. The goal is to maintain hemoglobin levels between 10-12 g/dL.
• Limitations: ESAs may be less effective in patients with high levels of inflammation, and some patients may develop resistance to ESAs, particularly in the presence of high hepcidin levels.

3. Iron Supplementation

Iron supplementation is generally not recommended in most cases of anemia of chronic disease, as iron is sequestered in macrophages and not readily available for erythropoiesis. However, in cases where iron deficiency coexists with anemia of chronic disease (e.g., in patients with gastrointestinal bleeding or malnutrition), iron supplementation may be necessary.

• Intravenous Iron: In patients who cannot absorb oral iron or who have significant iron deficiency alongside ACD, intravenous iron may be considered. However, caution is required, as excessive iron can exacerbate the inflammatory response.

4. Blood Transfusions

Blood transfusions may be required in severe cases of anemia or when rapid correction of hemoglobin is needed, such as before surgery or in patients with symptomatic anemia that does not respond to other therapies

• Risks: Frequent transfusions carry risks such as iron overload, alloimmunization, and transfusion reactions. Therefore, they should be used sparingly and only when necessary.

5. Hepcidin Modulators and Novel Therapies

Innovative therapies targeting the hepcidin-ferroportin axis are currently being developed to treat anemia of chronic disease. These agents aim to reduce hepcidin levels or inhibit its activity, thereby enhancing iron availability for erythropoiesis.

• Hepcidin Antagonists: These agents block the effects of hepcidin, allowing iron to be released from macrophages and absorbed from the gut. Hepcidin antagonists are still in the experimental stages but hold promise for treating ACD.
• Ferroportin Activators: By increasing the activity of ferroportin, these drugs aim to enhance iron export from macrophages and enterocytes, increasing iron availability for red blood cell production.

Innovative Treatments for Anemia of Chronic Disease

The evolving understanding of the pathophysiology of anemia of chronic disease has led to the development of novel therapies that target key regulatory mechanisms, such as hepcidin modulation and erythropoiesis stimulation. These treatments offer hope for patients who do not respond adequately to traditional therapies.

1. Roxadustat (HIF-PHI)

Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that stimulates endogenous erythropoietin production and enhances iron utilization. It is being investigated as a treatment for anemia in chronic kidney disease and may have potential applications in other forms of ACD.

• Mechanism of Action: Roxadustat increases erythropoietin production, improves iron absorption, and reduces hepcidin levels.
• Current Status: Approved in some countries for the treatment of anemia in CKD patients, Roxadustat is undergoing further studies to assess its efficacy in other forms of ACD.

2. Ferric Carboxymaltose

Ferric carboxymaltose is a newer intravenous iron preparation that has been shown to be effective in treating iron deficiency anemia, particularly in patients with heart failure, inflammatory bowel disease, and other chronic conditions associated with ACD.

• Benefits: Unlike oral iron, ferric carboxymaltose bypasses the gastrointestinal tract, providing a rapid replenishment of iron stores and improving hemoglobin levels in patients with ACD and concomitant iron deficiency.

3. GDF15 and TWSG1 Modulators

Research into the regulation of iron metabolism by growth differentiation factor 15 (GDF15) and twisted gastrulation protein 1 (TWSG1) has revealed potential therapeutic targets for ACD. Modulating these proteins may help overcome iron sequestration and improve erythropoiesis in patients with chronic inflammation.

• Future Directions: GDF15 and TWSG1 inhibitors are still in the early stages of development but represent a promising new approach to treating ACD.

Conclusion

Anemia of chronic disease is a complex and multifactorial condition that requires a comprehensive approach to diagnosis and management. Understanding the underlying mechanisms, such as iron dysregulation and impaired erythropoiesis, is key to selecting the most appropriate treatment strategies. While current management primarily focuses on addressing the underlying condition and using erythropoiesis-stimulating agents, innovative treatments such as hepcidin modulators and HIF stabilizers are showing promise in improving outcomes for patients with anemia of chronic disease.

Healthcare professionals must stay informed about these advances to provide optimal care and improve the quality of life for patients with ACD.