What is the cause of low ferritin (iron storage protein) levels with normal Transferrin Saturation (TSAT) in a patient?

Low Ferritin with Normal TSAT: Diagnostic Approach

Low ferritin with normal transferrin saturation most commonly indicates early-stage absolute iron deficiency where storage iron is depleted but circulating iron availability remains adequate for current erythropoiesis. 1

Understanding the Pathophysiology

Iron deficiency progresses through sequential stages, and your patient's laboratory pattern reflects the earliest phase:

• Ferritin depletion precedes low TSAT and anemia in the natural progression of iron deficiency, meaning storage iron (measured by ferritin) becomes depleted before circulating iron availability (measured by TSAT) drops below normal thresholds. 1

• Normal TSAT with low ferritin indicates that while iron stores are exhausted, the body is still maintaining adequate iron delivery to erythroid precursors by mobilizing remaining iron efficiently. 2

• This pattern does not rule out iron deficiency—it actually confirms early absolute iron deficiency before functional consequences develop. 1

Primary Causes to Investigate

Inadequate Iron Intake or Absorption

• Vegetarian or vegan diet is a leading cause of isolated ferritin depletion, as non-heme iron from plant sources has significantly lower bioavailability (2-20%) compared to heme iron from meat (15-35%). 1

• Proton pump inhibitor (PPI) use significantly impairs iron absorption by reducing gastric acid needed to convert ferric iron (Fe³⁺) to absorbable ferrous iron (Fe²⁺), and this is a critical reversible cause of oral iron resistance. 1

• Celiac disease causes iron malabsorption through villous atrophy in the duodenum (the primary site of iron absorption) and can present with isolated low ferritin without gastrointestinal symptoms—this must be screened with tissue transglutaminase antibodies. 1

• Chronic gastritis or H. pylori infection impairs iron absorption through reduced gastric acid production and direct competition for iron by the bacteria. 1

Increased Iron Losses

• Menstrual blood loss in premenopausal women accounts for 15-30 mg iron loss per cycle, and heavy menstrual bleeding can deplete iron stores faster than dietary intake can replenish them. 2

• Occult gastrointestinal bleeding from sources including gastritis, peptic ulcer disease, angiodysplasia, or malignancy must be excluded, particularly in patients over 50 years or with alarm symptoms. 1

• Blood donation causes 200-250 mg iron loss per unit, and frequent donors commonly develop isolated ferritin depletion. 2

Essential Diagnostic Workup

Immediate Laboratory Tests

• Celiac disease screening with tissue transglutaminase (TTG) antibodies is mandatory, as celiac disease is a common cause of refractory iron deficiency in young adults and frequently presents without gastrointestinal symptoms. 1

• H. pylori testing (stool antigen or urea breath test) should be performed to exclude infection-related malabsorption. 1

• High-sensitivity C-reactive protein (hs-CRP) must be checked to exclude occult inflammation that could mask true iron status, as inflammation elevates ferritin independent of iron stores. 1

• Complete blood count (CBC) to assess for anemia development and mean corpuscular volume (MCV), though anemia is a late finding and its absence does not exclude iron deficiency. 1

Medication and Dietary Review

• Document all acid-suppressing medications (PPIs, H2-receptor antagonists) with duration of use, as chronic acid suppression is a reversible cause of iron malabsorption. 1

• Detailed dietary history focusing on heme iron sources (red meat, poultry, fish) versus non-heme sources (legumes, fortified grains, vegetables). 1

• Assess for substances that inhibit iron absorption including calcium supplements, tea/coffee consumption with meals, and high-fiber intake. 1

Additional Testing if Initial Workup Negative

• Upper endoscopy should be considered if PPI use is chronic (>1 year) to evaluate for autoimmune atrophic gastritis, which impairs both iron and vitamin B12 absorption through loss of gastric parietal cells. 1

• Fecal occult blood testing or fecal immunochemical test (FIT) to screen for gastrointestinal blood loss if no other cause identified. 1

Critical Pitfalls to Avoid

• Do not assume normal TSAT excludes iron deficiency—this is the most common diagnostic error, as ferritin depletion is the earliest laboratory manifestation of iron deficiency and precedes abnormalities in TSAT or hemoglobin by weeks to months. 1

• Do not overlook celiac disease screening—this is a frequently missed diagnosis in young adults with refractory iron deficiency, and the condition can present with isolated iron deficiency without diarrhea or weight loss. 1

• Do not start iron supplementation without addressing PPI use—acid suppression will impair oral iron absorption and lead to treatment failure, requiring either PPI discontinuation or use of intravenous iron. 1

• Do not ignore the possibility of occult bleeding—even in young patients without alarm symptoms, gastrointestinal blood loss can cause isolated ferritin depletion before anemia develops. 1

Management Algorithm

Step 1: Address Reversible Causes

• Discontinue or reduce PPI therapy if clinically appropriate, or switch to H2-receptor antagonist which has less impact on iron absorption. 1

• Treat H. pylori infection if detected, as eradication improves iron absorption and allows oral iron supplementation to be effective. 1

• Implement gluten-free diet if celiac disease confirmed, which will restore intestinal absorption capacity within 3-6 months. 1

Step 2: Initiate Iron Supplementation

• Oral iron supplementation with ferrous sulfate 325 mg (65 mg elemental iron) once daily is the initial approach, taken on an empty stomach with vitamin C to enhance absorption. 1

• If no response to oral iron after 4-6 weeks (defined as ferritin increase <10 ng/mL or hemoglobin increase <1 g/dL), consider intravenous iron therapy with ferric carboxymaltose or iron sucrose. 1

• Target ferritin level >50 ng/mL to adequately replenish iron stores, not just correction of anemia if present. 1

Step 3: Monitoring and Follow-up

• Reassess ferritin and complete blood count every 1-2 months during treatment until ferritin reaches target level. 1

• Continue iron supplementation for 3-6 months after ferritin normalizes to fully replenish tissue iron stores. 1

• Investigate for ongoing blood loss if ferritin fails to rise despite adequate supplementation and correction of malabsorption causes. 1