What are the etiologies of low ferritin levels?

Causes of Low Ferritin Levels

Low ferritin levels result from absolute iron deficiency due to inadequate iron supply relative to demand, with the most common causes being chronic blood loss (menstrual, gastrointestinal), impaired absorption (celiac disease, atrophic gastritis, bariatric surgery), inadequate dietary intake, and increased physiologic demands (pregnancy). 1

Primary Mechanisms of Iron Depletion

Chronic Blood Loss

• Menstrual bleeding is the leading cause of iron deficiency in premenopausal women, affecting approximately 38% with non-anemic iron deficiency and 13% with iron-deficiency anemia. 1
• Gastrointestinal bleeding—whether overt or occult—represents the most common cause in men and postmenopausal women, often signaling underlying pathology including malignancy. 2
• Nonsteroidal anti-inflammatory drug use increases gastrointestinal blood loss and iron deficiency risk. 1

Impaired Iron Absorption

• Celiac disease accounts for 3–5% of all iron deficiency cases and is a frequent cause of treatment failure when undiagnosed. 2, 1
• Atrophic gastritis reduces gastric acid production, impairing iron absorption from dietary sources. 1
• Post-bariatric surgical anatomy (particularly Roux-en-Y gastric bypass) bypasses the duodenum where iron absorption is maximal. 2, 1
• Helicobacter pylori infection impairs intestinal iron absorption and should be screened in all iron-deficient patients. 2

Inadequate Dietary Iron Intake

• Vegetarian and vegan diets provide non-heme iron with lower bioavailability compared to heme iron from animal sources. 2
• Inadequate dietary iron intake alone rarely causes severe deficiency in developed countries but contributes when combined with other factors. 1

Increased Physiologic Demands

• Pregnancy increases iron requirements dramatically, with up to 84% of women in the third trimester developing iron deficiency in high-income countries. 1
• Infancy and adolescence represent periods of rapid growth with increased iron demands. 2
• Endurance athletes have elevated iron losses through hemolysis, gastrointestinal microbleeding, and increased erythropoietic demands. 2

Chronic Inflammatory Conditions

While chronic inflammatory diseases (inflammatory bowel disease, chronic kidney disease, heart failure, cancer) are associated with iron deficiency, these conditions typically present with functional iron deficiency (normal or elevated ferritin with low transferrin saturation) rather than low ferritin. 3, 1 When ferritin is truly low in these populations, it indicates coexistent absolute iron deficiency superimposed on the inflammatory state. 2

• Inflammatory bowel disease causes iron deficiency in 13–90% of patients through chronic intestinal blood loss and impaired absorption. 1
• Chronic kidney disease affects 24–85% of patients, primarily through functional deficiency, but absolute deficiency occurs with dialysis-related blood loss. 1
• Heart failure patients (37–61% affected) and cancer patients (18–82% affected) develop iron deficiency through multifactorial mechanisms including anorexia, malabsorption, and treatment-related blood loss. 1

Diagnostic Approach to Identify the Cause

Initial Laboratory Assessment

• Ferritin <15 μg/L has 99% specificity for absolute iron deficiency, confirming depleted stores without additional testing. 2
• Calculate transferrin saturation (serum iron × 100 ÷ TIBC); values <16–20% confirm iron deficiency and impaired iron delivery to bone marrow. 2
• Check inflammatory markers (CRP, ESR) to exclude falsely elevated ferritin masking true deficiency. 2

Mandatory Screening Tests

• Screen all iron-deficient patients for celiac disease with tissue transglutaminase IgA antibodies, given its 3–5% prevalence and high risk of treatment failure when missed. 2, 1
• Perform non-invasive H. pylori testing (stool antigen or urea breath test) in all cases. 2

Gastrointestinal Investigation

• In adult men and postmenopausal women, urgent bidirectional endoscopy (gastroscopy + colonoscopy) is mandatory because iron deficiency may be the sole manifestation of gastrointestinal malignancy. 2
• For premenopausal women, reserve endoscopy for: age ≥50 years, gastrointestinal symptoms (abdominal pain, altered bowel habits, visible bleeding), positive celiac or H. pylori testing, failure to respond to oral iron after 8–10 weeks, or strong family history of colorectal cancer. 2
• In young premenopausal women with heavy menstrual bleeding and no alarm features, empiric iron supplementation without immediate endoscopy is appropriate. 2

Critical Pitfalls to Avoid

• Do not assume dietary insufficiency alone in adults; chronic blood loss or malabsorption is present in the majority of cases and requires investigation. 1
• Do not overlook celiac disease screening—its 3–5% prevalence makes it a common missed diagnosis leading to treatment failure. 2
• Do not delay endoscopic evaluation in high-risk patients (men, postmenopausal women, age ≥50, alarm symptoms), as gastrointestinal malignancy can present solely with iron deficiency. 2
• Ferritin is an acute-phase reactant; inflammation, infection, or tissue damage can elevate ferritin levels independently of iron status, potentially masking depleted stores. 2, 4