What are the causes and treatment options for low normal ferritin levels?

Low Normal Ferritin: Causes and Management

What "Low Normal" Ferritin Actually Means

Low normal ferritin (15-50 μg/L) represents depleted iron stores that warrant treatment, even when hemoglobin remains normal. This is Stage 1 iron deficiency—the earliest and most specific marker of iron depletion before anemia develops 1.

• Ferritin <15 μg/L has 99% specificity for absolute iron deficiency 1
• Ferritin 15-30 μg/L indicates low body iron stores and generally warrants treatment 1
• Ferritin <45 μg/L provides optimal sensitivity-specificity balance (92% specificity) for clinical decision-making 1
• Many laboratories use reference ranges that miss iron deficiency in 30-50% of women, as these ranges are based on population distributions rather than physiologic iron needs 2

Primary Causes of Low Normal Ferritin

Increased Iron Loss

• Heavy menstrual bleeding is the leading cause in premenopausal women, affecting 38% with iron deficiency without anemia 3
• Gastrointestinal blood loss from NSAIDs, occult malignancy (9% of patients >65 years), peptic ulcer disease, or inflammatory bowel disease 4, 3
• Regular blood donation depletes iron stores over time 1

Inadequate Iron Intake or Absorption

• Dietary insufficiency in vegetarians, vegans, or those with eating disorders 5
• Malabsorption from celiac disease, atrophic gastritis, H. pylori infection, or post-bariatric surgery 3, 6
• Medications that reduce iron absorption, including proton pump inhibitors 6

Increased Iron Demand

• Pregnancy, especially third trimester (up to 84% prevalence in high-income countries) 3
• Adolescence during rapid growth phases 5
• High-performance athletes with increased erythropoietic demands 5

Chronic Inflammatory Conditions (with caveats)

• Inflammatory bowel disease (13-90% prevalence), chronic kidney disease (24-85%), heart failure (37-61%), and cancer (18-82%) can cause functional iron deficiency 3
• Critical caveat: In inflammatory states, ferritin is an acute-phase reactant that rises independently of iron stores, potentially masking true deficiency 1
• In these patients, ferritin <100 μg/L may still indicate iron deficiency 1

Diagnostic Algorithm

Step 1: Confirm Iron Deficiency Pattern

• Check complete blood count (hemoglobin, MCV, MCH) and serum ferritin 5
• If ferritin 15-50 μg/L with normal hemoglobin, this confirms nonanemic iron deficiency 1

Step 2: Rule Out Inflammation

• Measure C-reactive protein (CRP) to exclude false-normal ferritin from inflammation 5, 1
• If CRP elevated and ferritin 30-100 μg/L, calculate transferrin saturation (TSAT): (serum iron × 100) ÷ TIBC 1
• TSAT <16-20% confirms iron deficiency even with inflammation 1

Step 3: Identify the Source

For premenopausal women with heavy menses and no GI symptoms:

• Test for H. pylori and celiac disease serologies 3
• If negative and age <50 years, empiric iron supplementation is reasonable 3
• Reserve endoscopy for: positive testing, GI symptoms, persistent deficiency despite treatment, or age >50 years 3

For all other patients or those with alarm features:

• Bidirectional endoscopy (colonoscopy first if age >50) to exclude malignancy 4
• Alarm features requiring urgent evaluation: new/worsening abdominal pain, change in bowel habits, blood in stool, failure to respond to oral iron after 8-10 weeks 3

Treatment Protocol

First-Line: Oral Iron Supplementation

• Ferrous sulfate 325 mg daily (65 mg elemental iron) or ferrous bisglycinate 30-60 mg elemental iron daily 3, 7
• Alternate-day dosing (60 mg every other day) improves absorption and reduces GI side effects compared to daily dosing 3
• Take on empty stomach for optimal absorption; switch to with-meals if GI symptoms occur 3
• Expected side effects: constipation, nausea, diarrhea 3

When to Use Intravenous Iron

• Oral iron intolerance or malabsorption (celiac disease, post-bariatric surgery) 3
• Chronic inflammatory conditions (CKD, heart failure, IBD, cancer) 3
• Ongoing blood loss 3
• Second and third trimesters of pregnancy 3

Monitoring and Follow-Up

• Repeat CBC and ferritin in 8-10 weeks to assess response 3
• Expect hemoglobin increase of 1-2 g/dL if treatment is effective 4
• Target ferritin >100 ng/mL to restore iron stores and prevent recurrence 1
• If no improvement, consider malabsorption, non-compliance, ongoing blood loss, or need for IV iron 3

Long-Term Management for High-Risk Patients

• Screen ferritin every 6-12 months in menstruating females, vegetarians, athletes, and regular blood donors 1, 5
• Do not continue daily iron supplementation once ferritin normalizes—this is potentially harmful 5
• Consider intermittent oral supplementation to preserve iron stores in patients with recurrent low ferritin 5

Critical Clinical Pitfalls

• Do not dismiss ferritin 15-50 μg/L as "normal"—this represents depleted stores causing fatigue, exercise intolerance, restless legs syndrome (32-40%), and cognitive symptoms even without anemia 3, 1
• Do not use population-based reference ranges—physiologic ferritin cutoff is 50 ng/mL, and 30-50% of "healthy" women have no marrow iron stores 2
• Do not overlook inflammation—ferritin can be falsely elevated; always check CRP in patients with chronic disease 1
• Do not continue iron indefinitely—once ferritin normalizes, stop daily supplementation to avoid iron overload 5