What is the most likely diagnosis and next step for a patient with chest discomfort, fatigue, reduced exercise tolerance, normal hemoglobin, and normal echocardiogram, celiac serology, thyroid function tests, colonoscopy, and Helicobacter pylori testing?

Likely Diagnosis: Deconditioning vs. Iron Deficiency vs. Early Heart Failure with Preserved Ejection Fraction

The most likely diagnosis is deconditioning, but iron deficiency must be ruled out first by checking serum ferritin and transferrin saturation, followed by cardiopulmonary exercise testing (CPET) if iron studies are normal. 1, 2

Immediate Next Steps

1. Check Iron Studies (Priority #1)

• Order serum ferritin and transferrin saturation immediately 3, 4
• Iron deficiency without anemia is a common cause of fatigue, chest discomfort, and reduced exercise tolerance, affecting 14% of US adults 4
• Diagnostic thresholds:
  • Ferritin <30 μg/L defines iron deficiency without inflammation 3, 4
  • Transferrin saturation <20% confirms functional iron deficiency 3, 5
  • Normal hemoglobin does NOT exclude clinically significant iron deficiency 3, 4

Critical pitfall: Ferritin can be falsely elevated by inflammation, infection, or liver disease—always check CRP or ESR alongside ferritin to interpret results properly 3

2. If Iron Deficiency is Confirmed

• Treat with oral iron supplementation (ferrous sulfate 325 mg daily or alternate days) as first-line therapy 4
• Iron serves as a cofactor for ribonucleotide reductase, essential for DNA synthesis in high-turnover tissues 3
• Symptoms typically improve within 6 months of treatment initiation 3
• Monitor ferritin and hemoglobin every 3 months 3

3. If Iron Studies are Normal: Proceed to CPET

Cardiopulmonary exercise testing is the gold standard for differentiating between cardiac dysfunction, deconditioning, and other causes of exercise intolerance 1, 2

The ACC/AHA explicitly recommends maximal exercise testing when the contribution of heart failure is uncertain, as resting ventricular function (ejection fraction) correlates poorly with exercise capacity 1, 2

Differential Diagnosis Framework

Deconditioning (Most Likely if Iron Studies Normal)

CPET patterns that confirm deconditioning: 2

• Peak VO₂ at lower limit of normal
• Left-shifted heart rate-VO₂ relationship with steepened slope
• Reduced peak O₂ pulse
• Normal peak heart rate with little heart rate reserve
• Significant breathing reserve with normal PaO₂

Management: Exercise training for several weeks to months, starting gradually 2

Heart Failure with Preserved Ejection Fraction (HFpEF)

• 30% of patients with normal ejection fraction still have heart failure 1
• Exercise intolerance and fatigue are cardinal symptoms, but resting echo is often normal 1
• Key distinguishing features on history: 1
  • Orthopnea or paroxysmal nocturnal dyspnea
  • Leg swelling that worsens throughout the day
  • Weight gain or volume retention patterns

If HFpEF is suspected despite normal echo: Consider BNP/NT-proBNP measurement, though these may be normal in early HFpEF 1

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Consider if: 2

• Post-exertional malaise (symptom worsening after activity lasting >24 hours)
• Orthostatic intolerance symptoms
• Cognitive difficulties ("brain fog")

Critical management difference: Traditional graded exercise therapy is contraindicated in ME/CFS and can cause significant worsening 2

Why These Tests Were Already Done

The workup already completed appropriately ruled out:

• Celiac disease (can cause iron malabsorption and fatigue) 3
• Hypothyroidism (TSH normal rules out thyroid-related fatigue) 3
• GI bleeding (colonoscopy and H. pylori negative) 4
• Structural heart disease (echocardiogram normal) 1

However, normal hemoglobin does NOT exclude iron deficiency as a cause of symptoms—this is a common clinical pitfall 3, 4

Algorithmic Approach

1. Check ferritin + transferrin saturation + inflammatory markers (CRP/ESR) 3, 4

   • If ferritin <30 μg/L OR transferrin saturation <20%: Treat with oral iron 3, 4
   • If ferritin 30-100 μg/L with elevated CRP: Consider functional iron deficiency, may still benefit from iron 3

2. If iron studies normal: Order CPET 1, 2

   • Differentiates deconditioning from cardiac vs. pulmonary vs. ME/CFS causes
   • Provides objective exercise capacity measurement (peak VO₂)
   • Identifies ventilatory threshold to guide exercise prescription

3. If CPET shows deconditioning pattern: Initiate structured exercise program 2

   • Start conservatively and progress gradually
   • Monitor for post-exertional symptom worsening (would suggest ME/CFS instead)

4. If CPET suggests cardiac limitation despite normal resting echo: Consider advanced HF evaluation 1, 2

   • Exercise hemodynamics or stress echocardiography
   • BNP/NT-proBNP measurement
   • Possible HFpEF

Do not attribute symptoms to aging or anxiety without objective testing—this delays appropriate diagnosis and treatment 1, 2