Most Likely Diagnosis: Iron-Refractory Iron Deficiency Anemia (IRIDA)
The most likely diagnosis in this 23-year-old male is iron-refractory iron deficiency anemia (IRIDA), a genetic disorder caused by TMPRSS6 mutations that presents with remarkably low transferrin saturation, low-to-normal ferritin, microcytic hypochromic indices, and failure to respond to oral iron supplementation. 1
Rationale for IRIDA as Primary Diagnosis
Key Diagnostic Features Present
Remarkably low transferrin saturation (described as "low-borderline") combined with normal-to-high ferritin is the pathognomonic laboratory pattern of IRIDA, distinguishing it from typical iron deficiency anemia where both parameters are low. 1
Microcytic hypochromic indices (borderline low MCV, low MCH) with normal hemoglobin/hematocrit represent the early phase of IRIDA, where iron-restricted erythropoiesis causes red cell changes before overt anemia develops. 1
Low serum iron despite normal-to-high ferritin indicates functional iron deficiency—iron is sequestered in stores but unavailable for erythropoiesis due to elevated hepcidin from TMPRSS6 deficiency. 1, 2
Normal reticulocyte count confirms inadequate marrow response consistent with iron-restricted erythropoiesis rather than hemolysis or bleeding. 1
Low C-reactive protein excludes anemia of chronic disease, which requires elevated inflammatory markers and typically shows ferritin >100 µg/L with transferrin saturation <20%. 3, 2
Extensive Negative Workup Supports Genetic Etiology
Normal colonoscopy and negative H. pylori testing exclude gastrointestinal blood loss and malabsorption from atrophic gastritis. 1
Negative celiac serology rules out the most common malabsorption disorder causing iron deficiency (present in 2-3% of iron deficiency cases). 1
Normal thyroid function and normal echocardiogram eliminate secondary causes of fatigue and exercise intolerance. 1
The constellation of symptoms (chest discomfort, fatigue, reduced exercise tolerance) in a young male with iron-restricted erythropoiesis but extensive negative evaluation strongly points toward an inherited disorder. 1
Recommended Workup
Confirm IRIDA Diagnosis
Order genetic testing for TMPRSS6 mutations to definitively diagnose IRIDA, as this is the only genetic disorder that presents with low transferrin saturation and low-to-normal ferritin. 1
Measure soluble transferrin receptor (sTfR) if available—it will be elevated in IRIDA because tissue iron deficiency is present despite normal ferritin, and sTfR is not affected by inflammation. 3, 2
Calculate the ratio of serum iron to total iron-binding capacity to precisely quantify transferrin saturation; values <16% strongly confirm iron deficiency even with normal ferritin. 3, 1
Exclude Remaining Differential Diagnoses
Obtain hemoglobin electrophoresis to definitively rule out β-thalassemia trait, which can present with microcytosis and normal RDW (≤14%) but would show normal iron studies. 1
Check vitamin B12 and folate levels to exclude combined deficiencies, which can be suggested by elevated RDW despite normal values in this case. 1, 2
Consider bone marrow examination only if genetic testing is negative and the diagnosis remains unclear, as marrow iron staining can differentiate true iron deficiency from sideroblastic anemia. 1
Assess for Autoimmune Gastritis
Measure anti-parietal cell antibodies and anti-intrinsic factor antibodies to screen for autoimmune atrophic gastritis, which can cause oral iron refractoriness and must be excluded before attributing treatment failure to IRIDA. 1
Obtain serum gastrin level—elevated gastrin suggests atrophic gastritis even when H. pylori testing is negative. 1
Management Strategy
Initial Therapeutic Trial
Initiate oral ferrous sulfate 200 mg three times daily for 4 weeks as a diagnostic and therapeutic trial, even though IRIDA is suspected, because response patterns help confirm the diagnosis. 1
Recheck hemoglobin after 4 weeks—expect an increase of at least 2 g/dL if iron deficiency is responsive; failure to improve confirms iron refractoriness characteristic of IRIDA. 1
Monitor for gastrointestinal side effects and consider alternative oral formulations (ferrous gluconate or ferrous fumarate) if intolerance occurs, though this is less likely to improve absorption in IRIDA. 1
Definitive Treatment for IRIDA
Switch to intravenous iron (iron sucrose or ferric carboxymaltose) if oral iron fails to raise hemoglobin by ≥2 g/dL within 4 weeks, as IRIDA patients are refractory to oral iron but may respond partially to IV iron. 1
Administer IV iron in divided doses—a typical regimen is 500 mg initially, followed by 500 mg four weeks later, with monitoring of hemoglobin and ferritin. 2
Set realistic treatment goals—complete normalization of hemoglobin and ferritin is rarely achieved in IRIDA; aim for hemoglobin >11 g/dL and ferritin 50-100 µg/L to relieve symptoms. 1
Monitor ferritin closely during IV iron therapy—do not exceed 500 µg/L to avoid iron overload, especially in young patients requiring long-term treatment. 1
Long-Term Management
Repeat IV iron infusions every 3-6 months based on hemoglobin and ferritin trends, as IRIDA requires lifelong intermittent IV iron supplementation. 1
Avoid pyridoxine (vitamin B6) supplementation—this is effective only for X-linked sideroblastic anemia (ALAS2 defects), not IRIDA. 1
Do not pursue hematopoietic stem cell transplantation—this is reserved for severe congenital sideroblastic anemias (SLC25A38 defects) and is not indicated for IRIDA. 1
Critical Pitfalls to Avoid
Do not attribute normal-to-high ferritin to adequate iron stores—in IRIDA, ferritin is falsely reassuring because hepcidin elevation prevents iron mobilization from stores, creating functional iron deficiency. 1, 2
Do not delay genetic testing while pursuing additional GI investigations—the extensive negative workup (colonoscopy, celiac serology, H. pylori) already excludes common acquired causes, and further endoscopy is low-yield. 1
Do not assume treatment failure with oral iron indicates non-compliance—IRIDA is defined by oral iron refractoriness due to impaired duodenal iron absorption from elevated hepcidin. 1
Do not overlook the diagnosis in young males—IRIDA is autosomal recessive and affects both sexes equally, though it is often under-recognized in males because iron deficiency is typically attributed to menstrual blood loss in women. 1
Do not continue oral iron indefinitely without reassessment—if hemoglobin fails to rise after 4 weeks of adequate oral iron, switch to IV iron rather than prolonging ineffective therapy. 1