What are the causes of low ferritin and how does it interact with thyroid function?

Causes of Low Ferritin and Its Interaction with Thyroid Function

Primary Causes of Low Ferritin

Low ferritin results from four main mechanisms: chronic blood loss (the most common cause, accounting for ~94% of cases), impaired iron absorption, inadequate dietary intake, and increased physiological demand. 1, 2

Blood Loss

• Gastrointestinal bleeding is the leading cause in men and postmenopausal women and must be investigated urgently through bidirectional endoscopy to exclude malignancy 1, 2
• Menstrual blood loss accounts for iron deficiency in 38% of reproductive-age women (non-anemic) and 13% with iron-deficiency anemia 3
• Occult bleeding from nonsteroidal anti-inflammatory drug use, inflammatory bowel disease (13-90% prevalence), or other sources depletes stores over time 1, 3

Malabsorption Conditions

• Celiac disease is present in 3-5% of all iron-deficiency cases and causes treatment failure when missed; screen with tissue transglutaminase antibodies 4, 1
• Helicobacter pylori infection impairs iron absorption and should be tested non-invasively with stool antigen or urea-breath test 4, 1
• Atrophic gastritis (autoimmune or H. pylori-related) reduces gastric acid needed for iron absorption 5
• Post-bariatric surgery (especially gastric bypass) creates anatomical changes that limit iron absorption 1, 3

Dietary and Increased Demand

• Inadequate dietary iron is particularly problematic in vegetarians/vegans due to substantially lower bioavailability compared to meat-based diets 1
• Pregnancy increases iron requirements dramatically, with up to 84% of third-trimester women developing iron deficiency in high-income countries 3

Chronic Inflammatory Conditions

• Inflammatory bowel disease causes both malabsorption and chronic blood loss in 13-90% of patients 1, 3
• Chronic kidney disease (24-85% prevalence), heart failure (37-61%), and cancer (18-82%) create functional iron deficiency through inflammatory iron sequestration 3

Critical Diagnostic Pitfall: Inflammation Masks True Iron Deficiency

Ferritin is an acute-phase reactant that rises during inflammation, infection, or tissue damage, potentially masking depleted iron stores even when true iron deficiency exists. 4, 1

• In patients without inflammation, ferritin <30 μg/L confirms absolute iron deficiency 4, 1
• In patients with inflammation (elevated CRP/ESR), the diagnostic threshold shifts upward to ferritin <100 μg/L 4, 1
• When ferritin is 30-100 μg/L with elevated inflammatory markers, calculate transferrin saturation: TSAT <20% confirms iron deficiency despite seemingly "normal" ferritin 4, 1

Thyroid-Iron Interaction: The Bidirectional Relationship

Iron Deficiency Impairs Thyroid Function

Iron deficiency directly impairs thyroid hormone synthesis because thyroid peroxidase—the enzyme that catalyzes thyroid hormone production—is iron-dependent. While the provided evidence does not contain specific studies on thyroid-iron interaction, this is established general medical knowledge that explains why patients with iron deficiency may have:

• Reduced conversion of T4 to active T3
• Decreased thyroid peroxidase activity
• Blunted response to thyroid hormone replacement
• Symptoms overlapping with hypothyroidism (fatigue, cold intolerance, difficulty concentrating)

Hypothyroidism Worsens Iron Deficiency

Conversely, hypothyroidism can worsen iron deficiency through:

• Reduced gastric acid production (similar to atrophic gastritis mechanism)
• Decreased intestinal motility impairing iron absorption
• Heavy menstrual bleeding (menorrhagia) from anovulatory cycles

Clinical Implications

When evaluating a patient with fatigue and low ferritin, always check thyroid function (TSH, free T4) because the symptoms overlap substantially and both conditions may coexist. 3

• Treat iron deficiency first or simultaneously with thyroid replacement, as iron repletion may improve thyroid hormone synthesis
• Patients on levothyroxine with persistent symptoms despite "normal" TSH should have ferritin checked, as iron deficiency may prevent adequate T4-to-T3 conversion
• Conversely, patients with treated iron deficiency who remain symptomatic warrant thyroid screening

High-Risk Populations Requiring Vigilant Screening

• Menstruating females: Screen ferritin twice yearly 1
• Males and postmenopausal women: Annual ferritin assessment 1
• Vegetarians/vegans: Enhanced vigilance due to lower bioavailability 1
• Pregnant women: Up to 84% develop deficiency by third trimester 3
• Patients with IBD, CKD, heart failure, or cancer: Screen every 6-12 months 4, 1

Diagnostic Algorithm

1. Measure ferritin as the earliest and most specific marker of depleted iron stores 4
2. Check inflammatory markers (CRP, ESR) to interpret ferritin correctly 4, 1
3. Calculate transferrin saturation when ferritin is 30-100 μg/L or inflammation is present; TSAT <16-20% confirms iron deficiency 4, 1
4. Screen for celiac disease (tissue transglutaminase IgA) in all patients—present in 3-5% of cases 4, 1
5. Test for H. pylori non-invasively (stool antigen or urea-breath test) 4, 1
6. Investigate blood loss sources: bidirectional endoscopy in men and postmenopausal women; assess menstrual history in premenopausal women 1, 2
7. Check thyroid function (TSH, free T4) given symptom overlap and bidirectional interaction