What are the causes of low ferritin levels?

Causes of Low Ferritin

Low ferritin primarily results from inadequate iron intake, blood loss (menstrual or gastrointestinal), malabsorption disorders, increased physiological demands (pregnancy), or chronic inflammatory conditions that sequester iron. 1

Primary Mechanisms of Iron Depletion

Blood Loss

• Menstrual bleeding is the leading cause in reproductive-age women, with approximately 38% having iron deficiency without anemia and 13% having iron-deficiency anemia 1
• Gastrointestinal bleeding from any source (ulcers, malignancy, inflammatory bowel disease) must be investigated and excluded when iron deficiency is identified 2
• Chronic blood loss related to or unrelated to surgical procedures (particularly bariatric surgery) depletes iron stores over time 2

Inadequate Dietary Intake

• Insufficient dietary iron consumption is a fundamental cause, particularly in vegetarians/vegans where bioavailability is substantially lower than meat-based diets 2, 1
• Poor nutritional intake following bariatric surgery or due to dietary restrictions leads to inadequate iron to meet physiological needs 2
• The relationship between dietary iron intake and ferritin status can be obscured by diet reporting error and variations in bioavailability 3

Malabsorption Disorders

• Atrophic gastritis (autoimmune or Helicobacter pylori-related) impairs iron absorption 4
• Celiac disease significantly reduces iron absorption capacity 1
• Post-bariatric surgical procedures (particularly gastric bypass) create anatomical changes that limit iron absorption 2, 1
• Inflammatory bowel disease (affecting 13-90% of patients) causes both malabsorption and chronic blood loss 2, 1

Increased Physiological Demands

• Pregnancy dramatically increases iron requirements, with up to 84% of women in the third trimester developing iron deficiency in high-income countries 1
• Rapid growth periods in children (ages 9 months to 3 years and adolescence) increase iron demands beyond dietary supply 5
• Increased demand without adequate supplementation leads to progressive depletion of iron stores 4

Secondary and Contributing Factors

Medication-Related Causes

• Nonsteroidal anti-inflammatory drugs increase gastrointestinal blood loss risk 1
• Proton pump inhibitors reduce gastric acid necessary for iron absorption (general medical knowledge)
• Certain medications (anticonvulsants, sulfasalazine, methotrexate) may affect iron metabolism indirectly 2

Chronic Inflammatory Conditions

• Chronic kidney disease (affecting 24-85% of patients) causes functional iron deficiency where ferritin may be normal or elevated but iron is sequestered 1
• Heart failure (affecting 37-61% of patients) creates a state of iron dysregulation 1, 4
• Cancer (affecting 18-82% of patients) causes both increased utilization and inflammatory iron sequestration 1
• In inflammatory states, ferritin <100 μg/L may still indicate true iron deficiency despite the elevated threshold 2, 6

Rare Genetic Causes

• Iron-refractory iron deficiency anemia from TMPRSS6 mutations represents a very rare genetic cause of persistent iron deficiency 4
• Defective plasma iron transport is an uncommon mechanism 5

Critical Diagnostic Considerations

Interpreting Low Ferritin in Context

• Ferritin <15 μg/L has 99% specificity for absolute iron deficiency and confirms diagnosis definitively 2, 6
• Ferritin 15-30 μg/L indicates depleted iron stores requiring intervention 2, 6
• Ferritin is an acute-phase reactant that rises during inflammation, infection, or tissue damage, potentially masking true iron deficiency 2, 6, 7
• In inflammatory conditions, use transferrin saturation <16% as a complementary marker, as it indicates insufficient iron delivery despite potentially normal ferritin 2, 6

Common Clinical Pitfalls

• Failing to screen high-risk populations: menstruating females require twice-yearly screening, while males need annual assessment 2
• Overlooking inflammation: when CRP or ESR is elevated, ferritin thresholds shift upward to <100 μg/L for diagnosing iron deficiency 2, 6
• Missing occult blood loss: always investigate gastrointestinal sources when iron deficiency is unexplained, particularly in men and postmenopausal women 2
• Ignoring dietary patterns: vegetarian/vegan diets require enhanced vigilance due to lower iron bioavailability 2

Algorithmic Approach to Low Ferritin Etiology

Step 1: Confirm true iron deficiency

• Ferritin <15 μg/L = absolute iron deficiency confirmed 2, 6
• Check inflammatory markers (CRP, ESR) to adjust interpretation 2

Step 2: Identify blood loss sources

• Menstrual history in women 1
• Gastrointestinal evaluation (endoscopy if indicated) 2
• Occult bleeding assessment 2

Step 3: Assess absorption capacity

• History of bariatric surgery 2, 1
• Screen for celiac disease, atrophic gastritis 1, 4
• Evaluate for inflammatory bowel disease 2, 1

Step 4: Evaluate dietary intake and demands

• Dietary assessment (vegetarian/vegan status) 2, 1
• Pregnancy status 1
• Medication review (NSAIDs, PPIs) 1

Step 5: Consider chronic inflammatory conditions

• Assess for CKD, heart failure, cancer 1, 4
• If present, use transferrin saturation <20% as additional diagnostic criterion 2, 6