Anemia Of Chronic Disease: Symptoms, Types, Causes and Treatment

Anemia of Chronic Disease (ACD), sometimes known as anemia of inflammation, is a common and complex medical condition that frequently accompanies chronic illnesses such as infections, autoimmune disorders, cancers, and kidney disease. Understanding its symptoms, types, underlying causes, and the evolving landscape of treatments is essential for patients and healthcare providers alike. This comprehensive article breaks down what you need to know about ACD, using the latest scientific insights.

Symptoms of Anemia Of Chronic Disease

When living with a chronic condition, it can be easy to overlook symptoms like fatigue or weakness. However, these can be key indicators of anemia of chronic disease. The symptoms are often subtle and may overlap with those of the underlying illness, making careful observation and clinical awareness crucial for timely diagnosis and management.

Symptom	Description	Severity	Source(s)
Fatigue	Persistent tiredness, lack of energy	Mild to moderate	6, 10
Weakness	Reduced muscle strength, general malaise	Mild to moderate	5, 7
Shortness of Breath	Feeling breathless on exertion	Mild to moderate	5, 10
Pale Skin	Paleness, especially in the face	Mild	5, 10

Table 1: Key Symptoms

Recognizing ACD Symptoms

Unlike the dramatic symptoms of acute anemia, ACD typically develops gradually. This slow onset often means the body adjusts, so symptoms may seem less severe or are wrongly attributed to the underlying chronic illness.

Fatigue and Weakness

• The most common complaints are fatigue and generalized weakness. These symptoms stem from a reduced oxygen-carrying capacity of the blood, which impacts daily activities and overall quality of life 5 6 10.

Shortness of Breath

• Even mild anemia can cause noticeable breathlessness, especially during physical activity. This symptom is often misattributed to the underlying disease, such as heart or lung conditions 5 10.

Pale Skin and Other Subtle Signs

• Paleness, particularly in the face or nail beds, is a classic but often overlooked sign.
• Some patients may also experience dizziness, headaches, or an increased heart rate, though these are less common or more pronounced in severe cases.

Overlap with Underlying Disease

• Importantly, many symptoms of ACD overlap with those of the primary chronic illness. This overlap can delay diagnosis, emphasizing the need for clinical vigilance and appropriate laboratory testing 5 10.

Types of Anemia Of Chronic Disease

Anemia of chronic disease is not a "one size fits all" condition. It presents in various forms, depending on the underlying pathology, disease duration, and individual patient factors.

Type	Key Feature	Prevalence/Pattern	Source(s)
Normocytic	Normal RBC size and color	Most common	8, 12
Microcytic	Smaller, paler RBCs	30-50% of cases	8, 5
Mixed Forms	Coexistence with iron deficiency	Variable	6, 10

Table 2: Types of Anemia Of Chronic Disease

Classifying ACD

Normocytic, Normochromic Anemia

• In most patients, ACD presents as a normocytic, normochromic anemia—meaning red blood cells are of normal size and hemoglobin content. This is considered the classic form of ACD 8 12.

Microcytic, Hypochromic Anemia

• In 30–50% of patients, especially as the disease progresses or with coexistent iron deficiency, the anemia may become microcytic (small RBCs) and hypochromic (pale RBCs) 8 5.
• These cases can be more challenging to distinguish from iron deficiency anemia.

Mixed and Overlapping Types

• Some patients experience a blend, especially if they have both ACD and true iron deficiency (for example, due to chronic blood loss). This overlap can complicate the diagnosis and alter treatment strategies 6 10.

Disease-Specific Patterns

• The type can also vary with the underlying disease and its severity. For instance, chronic kidney disease may show a more pronounced decrease in erythropoietin production, influencing the anemia's characteristics 4 6.

Causes of Anemia Of Chronic Disease

ACD is fundamentally linked to chronic inflammation and the body’s immune response. Its pathogenesis is complex, involving altered iron metabolism, suppressed red blood cell production, and the effects of inflammatory cytokines.

Cause	Mechanism	Impact on Anemia	Source(s)
Chronic Inflammation	Cytokine & immune activation	Reduced RBC production	1, 2, 7
Hepcidin Overproduction	Iron sequestration, absorption block	Functional iron deficiency	2, 4, 5
Cytokines (IL-6, TNF)	Blunt erythropoietin, marrow suppression	Impaired erythropoiesis	7, 1, 12
Underlying Disease	Infection, autoimmune, cancer, CKD	Triggers inflammatory pathways	4, 5, 6, 12

Table 3: Major Causes and Mechanisms

The Underlying Science

Chronic Immune Activation

• ACD is most commonly triggered by chronic diseases that cause ongoing immune system activation—such as infections, autoimmune conditions (like rheumatoid arthritis), cancers, and chronic kidney disease 4 5 6 12.
• The body’s defense mechanisms, while aiming to fight disease, inadvertently disrupt normal blood production.

The Central Role of Hepcidin

• Hepcidin, a hormone produced by the liver, is the master regulator of iron metabolism. In ACD, inflammatory cytokines—especially interleukin-6 (IL-6)—stimulate excessive hepcidin production 2 4.
• Hepcidin binds to ferroportin (an iron export protein on cell surfaces), causing its degradation. This leads to iron being trapped inside cells (macrophages, hepatocytes), making it unavailable for new red blood cell production, despite normal or increased body iron stores—a phenomenon called "functional iron deficiency" 2 4 5.

Cytokine Effects

• Inflammatory cytokines (including IL-1, TNF, and interferons) not only increase hepcidin but also:
  • Suppress erythropoietin production (a hormone needed to stimulate RBC production in the bone marrow)
  • Impair the bone marrow’s ability to respond to erythropoietin
  • Shorten the survival of circulating red blood cells 1 7 12

Disease-Driven Pathways

• Each underlying disease can contribute unique elements:
  • Chronic kidney disease: Diminished erythropoietin production
  • Cancer: Bone marrow infiltration or suppression
  • Chronic infections: Heightened immune response and iron sequestration 4 5 12

Diagnosis: Exclusion and Biochemical Markers

• Diagnosing ACD requires excluding other causes of anemia, especially iron deficiency. Hallmark lab findings include:
  • Low serum iron and transferrin
  • Normal to high ferritin
  • Low reticulocyte count
  • Elevated inflammatory markers
• Newer tests, such as hepcidin assays and red cell indices, are increasingly used to improve diagnostic accuracy 5 13.

Treatment of Anemia Of Chronic Disease

Managing ACD is multifaceted, aiming not only to address the anemia itself but also the underlying chronic condition. Treatment is evolving, with both traditional and novel therapies in use and under investigation.

Approach	Focus/Mechanism	Considerations & Examples	Source(s)
Treat underlying cause	Reduces inflammation, reverses anemia	Infection control, cancer therapy	3, 12, 13
Iron therapy	Supplement iron stores	Oral/IV iron, assess for deficiency	5, 6, 13
Erythropoiesis stimulators	Boost RBC production	Erythropoietin, ESAs	4, 12, 13
Novel agents	Target hepcidin/iron metabolism	Hepcidin inhibitors, BMP/SMAD & JAK-STAT modulators	4, 11, 13
Blood transfusion	Rapid correction of anemia	For severe/symptomatic cases	12, 10

Table 4: Treatment Strategies

Approaches to Treatment

Addressing the Underlying Disease

• The most effective way to improve ACD is to treat the chronic condition causing it. When the underlying disease is controlled, inflammatory activity declines, and anemia often improves 3 12 13.
• Examples include:
  • Effective infection management
  • Immunosuppression in autoimmune diseases
  • Cancer therapy (chemotherapy, surgery)

Iron Supplementation

• Iron therapy is used cautiously. It's most beneficial when true iron deficiency coexists with ACD. Otherwise, supplemental iron—especially oral—may be ineffective due to blocked absorption from high hepcidin levels 5 6 13.
• Intravenous iron can be more effective in overcoming functional iron deficiency but must be balanced against the risk of promoting infections or tumor growth 5 13.

Erythropoiesis-Stimulating Agents (ESAs)

• ESAs, such as recombinant erythropoietin, can help stimulate red blood cell production when endogenous erythropoietin is inadequate or the marrow is unresponsive 4 12 13.
• Risks include hypertension and thromboembolic events, so careful patient selection is essential.

Novel and Emerging Therapies

• Recent advances focus on targeting the underlying mechanisms of ACD, particularly the hepcidin-ferroportin axis 4 11 13.
• Agents under investigation or early clinical use include:
  • Hepcidin antagonists (to improve iron availability)
  • BMP/SMAD and JAK-STAT pathway modulators (to reduce hepcidin production)
  • Molecularly targeted drugs like momelotinib, which reduces hepcidin and improves anemia in certain diseases 4 11

Blood Transfusions

• Reserved for severe cases or when rapid correction of anemia is needed. They are a temporary measure and do not address the underlying mechanism 12 10.

Supportive Care

• Nutritional supplementation (iron, folic acid, vitamin B12) may be indicated, especially when concomitant deficiencies are present 5.

Conclusion

Anemia of chronic disease is a widespread and challenging condition with complex causes, variable presentations, and evolving treatment options. Here’s what we covered:

• Symptoms are often mild and overlap with those of the underlying condition, including fatigue, weakness, and shortness of breath.
• Types range from classic normocytic anemia to microcytic forms, sometimes coexisting with other deficiencies.
• Causes center on chronic inflammation, with hepcidin-driven iron restriction and suppressed red cell production as key mechanisms.
• Treatment prioritizes managing the underlying chronic disease, with iron supplementation, erythropoiesis-stimulating agents, and novel therapies targeting hepcidin and cytokine pathways as additional strategies.

Key Points:

• ACD is the second most common anemia worldwide, closely tied to chronic inflammation and disease 5 13.
• Early recognition and accurate diagnosis are critical, given the symptom overlap with underlying conditions.
• Treatment is individualized, balancing benefits and risks, and the therapeutic arsenal is expanding with new molecular targets.
• Ongoing research promises more targeted and effective therapies for patients living with chronic disease and anemia.

Understanding ACD empowers patients and clinicians to work together for better outcomes and improved quality of life.