What causes low iron saturation?

What Causes Low Iron Saturation

Low iron saturation (transferrin saturation <20%) results from insufficient iron availability to saturate transferrin binding sites, most commonly due to depleted iron stores from blood loss, inadequate dietary intake, impaired absorption, or increased physiological demands. 1

Primary Mechanisms of Low Iron Saturation

Blood Loss (Most Common Cause)

• Menstrual bleeding is the leading cause in reproductive-age women, with approximately 38% having iron deficiency without anemia and 13% having iron-deficiency anemia 2
• Gastrointestinal bleeding occurs from peptic ulcer disease, inflammatory bowel syndrome, bowel cancer, or NSAID use 1, 2
• Occult GI blood loss can occur in infants sensitive to cow's milk and adults with hookworm infections (though uncommon in the United States) 1
• Pathological blood loss leads to depletion of iron stores before transferrin saturation drops, as the body prioritizes maintaining functional iron initially 1

Inadequate Dietary Intake

• Insufficient dietary iron is particularly problematic in vegetarian and vegan diets, where bioavailability is substantially lower than meat-based diets 1
• The recommended daily allowance is 18 mg (North America) or 14.8 mg (UK) for females, and 8 mg (North America) or 8.7 mg (UK) for males 1
• Heme iron sources (meat, seafood) have much higher bioavailability than non-heme sources 1

Impaired Iron Absorption

• Atrophic gastritis (autoimmune or Helicobacter pylori-related) reduces iron absorption 3, 2
• Celiac disease impairs intestinal iron uptake 2
• Bariatric surgical procedures reduce absorptive capacity 2
• Tea and coffee consumption around meal times inhibits iron absorption through polyphenols and tannins 1, 4
• Calcium-rich foods consumed simultaneously with iron sources reduce absorption 4

Increased Physiological Demands

• Pregnancy requires an average of 3 mg iron daily over 280 days' gestation, with up to 84% of pregnant women in the third trimester developing iron deficiency 1, 2
• Growth periods in infants and children increase iron requirements beyond dietary intake 1
• Preterm or low-birthweight infants are born with reduced iron stores despite normal iron-to-body-weight ratios 1

Chronic Inflammatory Conditions

Functional Iron Deficiency

• Chronic kidney disease (24-85% affected), heart failure (37-61%), inflammatory bowel disease (13-90%), and cancer (18-82%) cause functional iron deficiency where transferrin saturation remains low despite adequate or elevated ferritin 2, 5
• Inflammation increases hepcidin production, which blocks ferroportin and traps iron in storage sites, making it unavailable for erythropoiesis 5
• In these conditions, TSAT <20% with ferritin 100-300 ng/mL confirms iron deficiency despite seemingly "normal" ferritin levels 5

Rare Genetic Causes

• Iron-refractory iron deficiency anemia from TMPRSS6 mutations prevents adequate iron absorption despite supplementation 3
• Genetic hypotransferrinemia causes low transferrin-bound iron with paradoxical tissue iron overload 1
• SLC11A2 (DMT1) defects impair enterocyte and erythroid iron uptake, causing anemia with systemic iron loading 1

Physiological Context

Iron Recycling and Loss

• In adult men, approximately 95% of iron for red blood cell production comes from recycling senescent RBCs, with only 5% from dietary sources 1
• Daily iron losses average 1 mg in men through feces and desquamated cells, plus an additional 0.3-0.5 mg daily in menstruating women 1
• When long-term negative iron balance occurs, iron stores deplete first (measured by ferritin), followed by reduced transport iron (measured by transferrin saturation), and finally iron-deficiency anemia develops 1

Clinical Pitfalls to Avoid

• Do not rely on transferrin saturation alone—always measure serum ferritin concurrently, as TSAT is less sensitive to iron store depletion than ferritin 1, 5
• Account for diurnal variation—TSAT rises in the morning and falls at night, and increases after meals 1, 5
• Recognize inflammation's masking effect—infections and chronic inflammatory conditions can decrease serum iron and TSAT independent of true iron stores 1, 5
• Avoid testing within 4 weeks of IV iron infusion—circulating iron interferes with assay accuracy 5