In an adult with mild chest discomfort, fatigue, reduced exercise tolerance, normal hemoglobin and hematocrit, borderline low mean corpuscular volume, low mean corpuscular hemoglobin, normal red cell distribution width, normal reticulocyte count, low serum iron, low‑borderline transferrin saturation, normal‑to‑high ferritin and low C‑reactive protein, what is the most likely diagnosis and what work‑up and management should be pursued?

Functional Iron Deficiency in the Context of Cardiac Symptoms

Most Likely Diagnosis

This patient has functional iron deficiency (FID) causing symptomatic iron-restricted erythropoiesis, which is directly contributing to chest discomfort, fatigue, and exercise intolerance. 1 The laboratory pattern—low serum iron (10.4 µmol/L), low-borderline transferrin saturation (19%), normal-to-high ferritin (~330 ng/mL), low MCH (25.8 pg), and low CRP—indicates that iron stores are adequate but iron delivery to the bone marrow for hemoglobin synthesis is impaired. 2, 3

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Understanding the Laboratory Pattern

Iron Availability vs. Iron Storage

• Transferrin saturation of 19% is below the critical threshold of 20%, confirming insufficient iron available for red blood cell production despite adequate storage iron reflected by ferritin of 330 ng/mL. 1, 2
• Low MCH (25.8 pg) indicates reduced hemoglobin content per red cell, demonstrating that newly produced erythrocytes are iron-deficient even though total hemoglobin remains normal at 147 g/L. 1, 4
• Low serum iron (10.4 µmol/L) combined with low-borderline TSAT confirms impaired iron delivery to the bone marrow for hemoglobin synthesis. 2, 3
• Normal reticulocyte count (40) and reticulocyte hemoglobin (30.5) indicate bone marrow function is intact, ruling out primary marrow failure or erythropoietin deficiency. 1, 4
• Low CRP excludes anemia of chronic disease (inflammatory iron block), which would present with elevated inflammatory markers and sequestered iron in the reticuloendothelial system. 2, 5, 6

Why Ferritin is Normal-High Despite Iron Deficiency

• Ferritin of 330 ng/mL does not exclude functional iron deficiency; in FID, iron stores are present but cannot be mobilized rapidly enough to meet erythropoietic demands. 1, 2
• The key diagnostic parameter is transferrin saturation <20%, not ferritin, because TSAT reflects iron availability for erythropoiesis rather than total body stores. 1, 2, 3

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Clinical Significance of Functional Iron Deficiency

Symptom Correlation

• Iron deficiency without anemia causes significant symptoms including fatigue, reduced exercise tolerance, and chest discomfort, even when hemoglobin remains within normal range. 2, 7
• Reduced aerobic performance and exercise intolerance are common manifestations of iron-restricted erythropoiesis due to impaired oxygen delivery at the tissue level. 2, 7
• In patients with underlying cardiac conditions, functional iron deficiency exacerbates symptoms by reducing oxygen-carrying capacity and increasing cardiac workload. 1, 7

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Mandatory Cardiac Evaluation

Rule Out Structural Heart Disease

Given the triad of chest pain, fatigue, and exercise intolerance, urgent cardiac evaluation is required to exclude:

• Coronary artery disease: Perform stress testing or coronary CT angiography in patients with cardiac risk factors (age, diabetes, hypertension, family history). 1
• Heart failure with preserved ejection fraction (HFpEF): Check NT-proBNP and echocardiography; iron deficiency is highly prevalent in HFpEF and independently worsens functional capacity. 1, 7
• Valvular heart disease or cardiomyopathy: Echocardiography is essential to assess structural abnormalities. 1
• Congenital heart disease with cyanosis: Although hemoglobin is normal here, the low MCH pattern can occur in cyanotic patients with iron deficiency; however, this is unlikely given normal oxygen saturation would be expected to be documented. 1

Iron Deficiency in Heart Failure

• In patients with NYHA class II-III heart failure and iron deficiency (ferritin <100 ng/mL or 100-300 ng/mL with TSAT <20%), intravenous iron replacement is reasonable (Class IIb recommendation) to improve functional status and quality of life. 1
• Iron deficiency is independently associated with reduced exercise capacity in heart failure, and correction improves 6-minute walk distance and NYHA class. 1

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Diagnostic Work-Up

Immediate Laboratory Assessment

1. Measure NT-proBNP or BNP to screen for heart failure; elevated levels warrant echocardiography. 1
2. Confirm transferrin saturation calculation: TSAT = (serum iron × 100) ÷ TIBC. A TSAT of 19% confirms functional iron deficiency. 2, 3
3. Repeat complete blood count to document MCV, MCH, and RDW trends; progressive microcytosis suggests worsening iron-restricted erythropoiesis. 1
4. Check thyroid function (TSH, free T4) because hypothyroidism can cause fatigue, exercise intolerance, and coexist with iron deficiency. 1

Screen for Occult Blood Loss

• In adult men and post-menopausal women, functional iron deficiency with low serum iron warrants gastrointestinal investigation to exclude occult bleeding from malignancy, angiodysplasia, or NSAID-induced gastropathy. 1, 2
• Screen for celiac disease with tissue transglutaminase IgA antibodies; celiac disease is present in 3-5% of iron-deficiency cases and impairs iron absorption. 1, 2
• Test for Helicobacter pylori infection (stool antigen or urea-breath test) because it impairs iron absorption. 1, 2
• Reserve bidirectional endoscopy (upper endoscopy + colonoscopy) for: age ≥50 years, gastrointestinal symptoms (abdominal pain, altered bowel habits, visible blood), positive celiac or H. pylori testing, or lack of response to oral iron after 8-10 weeks. 1, 2

Assess for Malabsorption

• Celiac disease screening is mandatory because untreated celiac disease prevents iron absorption and causes treatment failure. 1, 2
• Consider inflammatory bowel disease if there is a history of diarrhea, abdominal pain, or weight loss. 2, 6

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Treatment Protocol

Oral Iron Supplementation

Initiate oral ferrous sulfate providing 65 mg elemental iron daily (or 60-65 mg every other day) immediately, without waiting for completion of diagnostic work-up. 2

• Alternate-day dosing (60 mg every other day) improves absorption by 30-50% and reduces gastrointestinal side effects compared to daily dosing. 2
• Take on an empty stomach for optimal absorption, or with meals if gastrointestinal symptoms (nausea, constipation, diarrhea) occur. 2
• Expected hematologic response: hemoglobin should rise by ≥10 g/L within 2 weeks of starting therapy; absence of this rise suggests malabsorption, non-compliance, or ongoing blood loss. 2

Indications for Intravenous Iron

Switch to intravenous ferric carboxymaltose (15 mg/kg, maximum 1000 mg per dose) if any of the following apply: 2

• Oral iron intolerance (severe nausea, constipation, diarrhea)
• Confirmed malabsorption (celiac disease, inflammatory bowel disease, post-bariatric surgery)
• Ongoing blood loss exceeding oral replacement capacity
• Chronic heart failure with NYHA class II-III symptoms and TSAT <20% (Class IIb recommendation for functional status improvement) 1
• Lack of hemoglobin response after 8-10 weeks of adequate oral iron 2

Intravenous iron produces reticulocytosis within 3-5 days and yields a mean hemoglobin increase of approximately 8 g/L over 8 days, demonstrating superior efficacy in indicated populations. 2

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Monitoring and Follow-Up

Short-Term Monitoring

• Repeat complete blood count and ferritin at 8-10 weeks to assess response to oral iron therapy. 2
• Target ferritin >100 ng/mL and TSAT >20% to fully replenish iron stores and restore iron availability for erythropoiesis. 1, 2
• Continue oral iron for 3 months after hemoglobin normalizes to achieve target ferritin and prevent rapid recurrence. 2

Long-Term Surveillance

• For high-risk groups (menstruating females, vegetarians, athletes, regular blood donors), screen ferritin every 6-12 months to detect early depletion before anemia develops. 2
• Do not continue daily iron supplementation once ferritin normalizes, as this is potentially harmful. 2

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Critical Pitfalls to Avoid

Misinterpretation of Laboratory Values

• Do not assume normal ferritin excludes iron deficiency; transferrin saturation <20% is the key parameter for assessing iron availability for erythropoiesis, regardless of ferritin level. 1, 2, 3
• Do not overlook functional iron deficiency in patients with normal hemoglobin; symptoms of fatigue and exercise intolerance can be severe even without anemia. 2, 7
• Low MCH (25.8 pg) is a sensitive early marker of iron-restricted erythropoiesis and should prompt investigation even when hemoglobin is normal. 1, 4

Delayed Cardiac Evaluation

• Do not attribute chest pain and exercise intolerance solely to iron deficiency without excluding cardiac disease; coronary artery disease, heart failure, and valvular disease must be ruled out. 1
• In patients with confirmed heart failure and iron deficiency (TSAT <20%), intravenous iron improves functional capacity and quality of life (Class IIb recommendation). 1

Incomplete Investigation of Iron Loss

• Do not overlook celiac disease screening; its 3-5% prevalence in iron-deficiency cases can lead to treatment failure if not identified. 1, 2
• In adult men and post-menopausal women, failure to investigate gastrointestinal blood loss may miss occult malignancy presenting solely with iron deficiency. 1, 2
• Do not delay endoscopic evaluation in high-risk patients (age ≥50 years, alarm symptoms, treatment failure after 8-10 weeks of oral iron). 1, 2