Is a slowly progressive anemia concerning?

Evaluation of Slowly Progressive Anemia

A slowly progressive anemia with a decline from 12.12 g/dL to 10.5 g/dL over a 3-year period is concerning and warrants a thorough evaluation to determine the underlying cause. This pattern of gradual hemoglobin decline requires investigation as it may indicate an underlying pathological process.

Assessment of Hemoglobin Trend

The patient's hemoglobin values show a consistent downward trend:

• 12.12 g/dL (Duke 2022)
• 12.6 g/dL (UNC 2023)
• 11.5 g/dL (UNC 2024)
• 11.4 g/dL (UNC 2025)
• 10.5 g/dL (Duke 2025)

This represents a decline of 1.62 g/dL over approximately 3 years, which exceeds what would be expected from normal physiological variation.

Diagnostic Approach

According to guidelines, anemia is defined as hemoglobin less than 13.5 g/dL in adult males and less than 12.0 g/dL in adult females 1. The current value of 10.5 g/dL meets the criteria for anemia regardless of gender.

Initial Laboratory Evaluation:

1. Complete iron studies:

   • Serum ferritin (target >100 μg/L with inflammation, >30 μg/L without inflammation)
   • Transferrin saturation (target >16%)
   • Total iron binding capacity (TIBC)
   • Serum iron

2. Inflammatory markers:

   • C-reactive protein (CRP)
   • Erythrocyte sedimentation rate (ESR)

3. Additional tests:

   • Complete blood count with reticulocyte count
   • Vitamin B12 and folate levels
   • Kidney function tests (BUN, creatinine, eGFR)
   • Liver function tests
   • Thyroid function tests

Differential Diagnosis

Based on the slowly progressive pattern, consider:

1. Iron deficiency anemia:

   • Most common cause of anemia worldwide
   • Check ferritin, transferrin saturation, and RDW 2

2. Anemia of chronic disease/inflammation:

   • Characterized by ferritin >100 μg/L, low transferrin saturation (<20%), and low/normal TIBC 2
   • Associated with chronic inflammatory conditions

3. Chronic kidney disease:

   • Anemia prevalence increases with declining kidney function
   • Significant when GFR <60 mL/min/1.73 m² (stage 3 CKD) 1

4. Vitamin B12 or folate deficiency:

   • Check MCV for macrocytosis
   • Serum B12 <200 pg/mL or folate deficiency 3

5. Bone marrow disorders:

   • Consider if other cell lines affected
   • May require bone marrow biopsy if other causes ruled out

Management Approach

Iron Deficiency:

• If ferritin <30 μg/L or <100 μg/L with inflammation and transferrin saturation <16%:
  • Oral iron: Ferrous sulfate 324 mg (65 mg elemental iron) 2-3 times daily
  • Continue treatment for 2-3 months after hemoglobin normalization 2
  • Consider IV iron if oral not tolerated or ineffective

Anemia of Chronic Disease:

• Identify and treat underlying inflammatory condition
• Iron supplementation only if concurrent absolute iron deficiency exists 2

Chronic Kidney Disease:

• Monitor hemoglobin at least annually in CKD patients 1
• More frequent monitoring with progressive decline
• Consider erythropoiesis-stimulating agents if symptomatic and Hb <10 g/dL

B12/Folate Deficiency:

• For B12 deficiency: Hydroxocobalamin 1 mg IM three times weekly for 2 weeks, then 1 mg IM every 2-3 months 2
• For folate deficiency: Oral folate 1-5 mg daily

Monitoring and Follow-up

• Repeat hemoglobin and reticulocyte count in 4-8 weeks to assess response to therapy
• Monitor iron studies every 3 months until stable
• Annual surveillance for patients with stable anemia
• More frequent monitoring (every 3-6 months) for those with progressive decline

Important Considerations

• The natural history of anemia in chronic conditions is a gradual decline in hemoglobin over time 1
• A decline of >1.5 g/dL over 3 years, as seen in this case, exceeds what would be expected from normal aging alone
• Anemia is not a normal consequence of aging and should always be investigated 1
• Failure to identify and treat the underlying cause can lead to worsening symptoms and complications, including cardiac stress and left ventricular hypertrophy 4

Pitfalls to Avoid

• Misinterpreting ferritin levels in inflammatory states (ferritin is an acute phase reactant) 2
• Relying solely on MCV for diagnosis without complete iron studies
• Failing to consider combined etiologies (e.g., iron deficiency with anemia of chronic disease)
• Attributing anemia to age without proper investigation
• Overlooking occult blood loss as a cause of iron deficiency

This progressive anemia requires thorough evaluation and should not be dismissed as a normal finding, regardless of the patient's age or comorbidities.