Chronic Disease

Overview of Anemia of Chronic Disease (ACD)

Definition: Anemia associated with chronic inflammatory, infectious, or malignant conditions
Alternative Name: Anemia of Inflammation
Characteristics:
- Typically normocytic and normochromic, but can be microcytic in some cases
- Characterized by impaired iron utilization and decreased red blood cell production
Prevalence: Second most common cause of anemia worldwide, after iron deficiency anemia

Etiology and Associated Conditions

Chronic Inflammatory Conditions:
- Rheumatoid arthritis
- Systemic lupus erythematosus (SLE)
- Inflammatory bowel disease (IBD): Crohn’s disease and ulcerative colitis
- Chronic infections: Tuberculosis (TB), HIV, osteomyelitis
Malignancies:
- Cancer
- Lymphoma
- Multiple myeloma
Chronic Kidney Disease (CKD):
- Decreased erythropoietin (EPO) production
- Accumulation of uremic toxins
Chronic Heart Failure:
- Reduced renal perfusion and EPO production
- Inflammatory cytokines

Pathophysiology

Iron Dysregulation:
- Hepcidin: A key hormone in iron regulation, produced by the liver
  - In ACD, chronic inflammation leads to increased hepcidin production
  - Hepcidin binds to ferroportin, the iron export protein found on enterocytes, macrophages, and hepatocytes
  - Binding of hepcidin to ferroportin causes ferroportin internalization and degradation, which:
    - Inhibits iron absorption in the gut
    - Blocks the release of iron from macrophages (where iron is recycled from senescent RBCs)
    - Traps iron in hepatocytes
  - Result: Decreased iron availability for erythropoiesis, despite adequate iron stores
- Iron-Restricted Erythropoiesis:
  - Limited iron availability impairs hemoglobin synthesis, leading to decreased RBC production
  - Erythroid progenitors in the bone marrow are unable to acquire sufficient iron for hemoglobin production
Decreased Erythropoietin (EPO) Production and Response:
- Suppressed EPO Production:
  - Inflammatory cytokines (e.g., IL-1, TNF-α) can suppress EPO production in the kidneys
- Impaired EPO Response:
  - Inflammatory cytokines can also blunt the response of erythroid progenitors to EPO
  - Mechanisms may involve interference with EPO receptor signaling
Shortened Red Blood Cell Survival:
- Inflammatory cytokines can increase red blood cell destruction, leading to a slightly shortened RBC lifespan

Clinical Manifestations

Symptoms of Anemia:
- Fatigue
- Weakness
- Pallor (pale skin)
- Shortness of breath
- Dizziness
Symptoms of Underlying Condition:
- The clinical presentation is often dominated by the symptoms of the underlying chronic disease (e.g., joint pain in rheumatoid arthritis, diarrhea and abdominal pain in IBD)

Diagnostic Evaluation

Complete Blood Count (CBC):
- Hemoglobin (HGB): Decreased (typically mild to moderate anemia)
- Hematocrit (HCT): Decreased
- Mean Corpuscular Volume (MCV): Usually normal (normocytic) but can be low (microcytic) in some cases, especially in long-standing ACD or when coexisting with iron deficiency
- Mean Corpuscular Hemoglobin Concentration (MCHC): Usually normal (normochromic)
- Red Cell Distribution Width (RDW): Usually normal
- Reticulocyte Count: Low or normal (inappropriately low for the degree of anemia)
Peripheral Blood Smear:
- Usually normocytic and normochromic
- May show mild anisocytosis (variation in RBC size) and poikilocytosis (variation in RBC shape)
Iron Studies:
- Serum Iron: Low
- Total Iron-Binding Capacity (TIBC): Normal or low
- Transferrin Saturation: Normal or low
- Ferritin: Normal or elevated (this helps distinguish ACD from iron deficiency anemia)
Markers of Inflammation:
- Erythrocyte Sedimentation Rate (ESR): Elevated
- C-Reactive Protein (CRP): Elevated
- Other inflammatory markers: IL-6, TNF-α
Other Tests:
- Serum erythropoietin (EPO) level: May be low or inappropriately normal for the degree of anemia
- Tests to evaluate underlying chronic conditions:
  - Rheumatoid factor, anti-CCP antibodies (for rheumatoid arthritis)
  - Antinuclear antibody (ANA) (for SLE)
  - Stool studies, colonoscopy (for IBD)
  - Chest X-ray, sputum culture (for TB)
- Bone Marrow Aspiration and Biopsy:
  - May be performed to rule out other causes of anemia or to evaluate for MDS

Differential Diagnosis

Iron Deficiency Anemia (IDA):
- Microcytic, hypochromic anemia with low serum iron, high TIBC, low transferrin saturation, and low ferritin
Thalassemia:
- Microcytic anemia with normal or elevated iron studies and abnormal hemoglobin electrophoresis
Sideroblastic Anemia:
- Microcytic or normocytic anemia with elevated serum iron and ferritin, and ringed sideroblasts in the bone marrow
Anemia of Chronic Kidney Disease:
- Normocytic anemia with low EPO level and evidence of kidney dysfunction
Aplastic Anemia:
- Pancytopenia (decreased RBCs, WBCs, and platelets) and hypocellular bone marrow

Treatment and Management

Treat the Underlying Condition:
- The primary goal is to treat the underlying inflammatory, infectious, or malignant disease
- Effective treatment of the underlying condition may improve the anemia
Erythropoiesis-Stimulating Agents (ESAs):
- Epoetin alfa or darbepoetin alfa
- May be used to stimulate red blood cell production, especially in patients with CKD or cancer-related anemia
- Use ESAs cautiously due to potential side effects:
  - Increased risk of thromboembolic events (blood clots)
  - Increased mortality in some cancer patients
  - ESAs are typically used when hemoglobin levels are below 10 g/dL and other causes of anemia have been ruled out
- Iron supplementation is often necessary to ensure an adequate response to ESAs
Iron Supplementation:
- Oral iron supplementation is generally not effective in ACD due to hepcidin-mediated iron restriction
- Intravenous (IV) iron may be considered in selected patients who are iron-deficient or who are receiving ESAs
- Monitor iron studies to avoid iron overload
Blood Transfusions:
- Reserved for patients with severe anemia and significant symptoms
- Goal is to alleviate symptoms and improve oxygen delivery to tissues
Novel Therapies:
- Hepcidin antagonists:
  - Inhibit hepcidin activity, promoting iron release and improving erythropoiesis
- Inhibition of inflammatory cytokines:
  - Targeting IL-6 or TNF-α to reduce inflammation and improve iron utilization

Key Laboratory Findings

Complete Blood Count (CBC):
- Mild to moderate anemia (low HGB and HCT)
- Usually normocytic and normochromic (normal MCV and MCHC)
- Low or normal reticulocyte count
Peripheral Blood Smear:
- Usually normal, but may show mild anisocytosis and poikilocytosis
Iron Studies:
- Low serum iron
- Normal or low TIBC
- Normal or low transferrin saturation
- Normal or elevated ferritin (key differentiating factor from iron deficiency anemia)
Markers of Inflammation:
- Elevated ESR and CRP
Erythropoietin (EPO) Level:
- May be low or inappropriately normal for the degree of anemia

Key Terms

Anemia of Chronic Disease (ACD): Anemia associated with chronic inflammatory, infectious, or malignant conditions
Hepcidin: Hormone that regulates iron homeostasis
Ferritin: Iron storage protein
TIBC (Total Iron-Binding Capacity): Measures the blood’s capacity to bind iron
Transferrin Saturation: Percentage of transferrin bound to iron
Erythropoietin (EPO): Hormone that stimulates red blood cell production
Erythropoiesis-Stimulating Agents (ESAs): Medications used to stimulate red blood cell production
Iron-Restricted Erythropoiesis: Impaired red blood cell production due to limited iron availability

Iron Deficiency

Thalassemias