Why does a patient with hypoferritinemia (low ferritin level) experience fatigue despite having normal iron and hemoglobin levels?

Why Fatigue Occurs with Low Ferritin Despite Normal Iron and Hemoglobin

Iron deficiency without anemia (low ferritin with normal hemoglobin) causes fatigue because iron is essential for cellular energy metabolism, neurotransmitter synthesis, and mitochondrial function—not just oxygen transport. 1

Understanding the Physiology

Iron serves critical functions beyond hemoglobin synthesis that directly impact energy and cognition:

• Iron is a critical constituent of many enzymes involved in cellular energy production, including those in the mitochondrial electron transport chain, which explains why fatigue occurs even before anemia develops 2
• Depleted iron stores (reflected by ferritin <30 ng/mL) cause significant symptoms including fatigue and lethargy even without anemia, as the body prioritizes iron for hemoglobin production over other tissues 3, 1
• Iron deficiency progresses through stages: Stage 1 involves depleted iron stores (low ferritin) with normal hemoglobin, where symptoms can already manifest 3

Clinical Manifestations Beyond Anemia

Patients with isolated low ferritin commonly experience:

• Fatigue, irritability, depression, and difficulty concentrating are well-documented symptoms of nonanemic iron deficiency 1
• Reduced physical performance and exercise intolerance occur because iron-dependent enzymes in muscle tissue cannot function optimally 3, 2
• Restless legs syndrome (32-40% of iron-deficient patients) and pica (40-50%) may be present 1
• Cognitive impairment results from iron's role in neurotransmitter synthesis and myelin production 2

Diagnostic Thresholds and Interpretation

Your ferritin of 5 ng/mL is severely depleted:

• Ferritin <15 ng/mL has 99% specificity for absolute iron deficiency and confirms the diagnosis definitively 3
• Ferritin <30 ng/mL indicates depleted body iron stores and warrants treatment even with normal hemoglobin 3, 2, 1
• Low ferritin is the earliest and most specific marker of iron deficiency, appearing before other parameters become abnormal 3

Critical Caveat About "Normal" Iron Studies

The term "normal iron" requires clarification:

• Serum iron shows diurnal variation and reflects only iron currently in transit, not total body stores 3
• Transferrin saturation (TSAT) should be calculated: values <16-20% confirm iron deficiency even when serum iron appears "normal" 3
• Hemoglobin remains normal in Stage 1 iron deficiency because the body sacrifices iron stores and tissue iron to maintain red blood cell production 3

Treatment Algorithm

For ferritin <15 ng/mL with symptoms, initiate oral iron supplementation immediately 3:

• Ferrous sulfate 325 mg daily or on alternate days is first-line therapy 1
• Preparations with 28-50 mg elemental iron are appropriate to minimize gastrointestinal side effects while maintaining compliance 2
• Repeat ferritin and hemoglobin after 8-10 weeks to assess response 2

When to Consider Intravenous Iron

Intravenous iron is indicated for 1:

• Oral iron intolerance or poor absorption (celiac disease, post-bariatric surgery)
• Chronic inflammatory conditions (CKD, heart failure, IBD)
• Ongoing blood loss
• Pregnancy (second and third trimesters)

Investigation for Underlying Cause

With ferritin this low, investigate the source of iron loss 3:

• Menstrual blood loss (most common in reproductive-age women) 1
• Gastrointestinal bleeding (especially if male or postmenopausal female) 1
• Malabsorption (atrophic gastritis, celiac disease, bariatric surgery) 1
• Inadequate dietary intake (vegetarian/vegan diet, eating disorders) 2, 1

Rule Out Inflammation

Before attributing symptoms solely to iron deficiency, check C-reactive protein (CRP) to exclude false-negative results 2:

• Ferritin is an acute-phase reactant that rises with inflammation, potentially masking true iron deficiency 3
• If CRP is elevated, ferritin thresholds shift upward to <100 ng/mL in inflammatory conditions 3

Long-Term Management

After initial correction, monitor ferritin every 6-12 months to prevent recurrence 3, 2:

• Patients with recurrent low ferritin benefit from intermittent oral supplementation to preserve iron stores 2
• Dietary counseling: integrate heme iron sources, look for enhancers (vitamin C), and avoid inhibitors (tea, coffee, calcium) of iron absorption 2
• Long-term daily supplementation with normal or high ferritin is not recommended and is potentially harmful 2