What are the next steps for a patient with low ferritin levels, improved hemoglobin A1c, and genetic testing showing heterozygous variants in the HFE gene, but no symptoms of iron deficiency anemia?

Management of Low Ferritin Without Anemia and Heterozygous HFE Variants

This patient requires iron supplementation to treat iron deficiency, reassurance regarding hemochromatosis risk, and investigation for the underlying cause of declining ferritin levels. 1, 2

Hemochromatosis Risk Assessment

The patient can be definitively reassured that heterozygous HFE variants (187C>G and 193A>T, corresponding to H63D and C282Y heterozygosity) do not cause hereditary hemochromatosis or progressive iron overload. 3

• C282Y heterozygotes and H63D heterozygotes are not at risk for developing progressive or symptomatic iron overload 3
• These genotypes may act as cofactors for liver disease when combined with other conditions (hepatitis C, alcohol-related liver disease, NAFLD), but do not independently cause iron accumulation 3
• The current presentation of declining ferritin (from 32 to 14 ng/mL) with normal transferrin saturation (26-30%) confirms absence of iron loading and is entirely inconsistent with any hemochromatosis phenotype 3
• Genetic counseling, while mentioned in standard laboratory language, is not clinically necessary for simple heterozygous carriers 3

Iron Deficiency Diagnosis and Treatment

Iron supplementation should be initiated immediately, as ferritin <30 ng/mL confirms absolute iron deficiency even without anemia. 1, 2

Oral Iron Supplementation Protocol

• Prescribe ferrous sulfate 325 mg daily or on alternate days (alternate-day dosing improves absorption and reduces gastrointestinal side effects) 1, 2
• Take with vitamin C (orange juice, ascorbic acid) to enhance non-heme iron absorption 1
• Avoid concurrent intake with tea, coffee, or calcium-containing foods/supplements 1
• Target ferritin level: 50-100 μg/L 1

Monitoring Schedule

• Recheck serum ferritin and hemoglobin after 8-10 weeks of treatment 1
• If ferritin remains low despite adequate compliance, consider malabsorption or ongoing iron loss 1, 2
• Continue monitoring ferritin every 6 months during treatment until target achieved 1

Investigation for Underlying Cause

The declining ferritin (32→14 ng/mL) mandates evaluation for occult blood loss or malabsorption, even in asymptomatic patients. 3, 2

Essential Initial Workup

• Urinalysis or urine microscopy to exclude urinary blood loss 3
• Celiac disease serological screening (tissue transglutaminase antibody with IgA level), as celiac disease is found in 3-5% of iron deficiency cases 3
• Detailed menstrual history if applicable (heavy menstrual bleeding is the most common cause in reproductive-age women) 2
• Review medications, particularly NSAIDs, aspirin, or anticoagulants 2

Gastrointestinal Evaluation Considerations

While the patient is asymptomatic and not anemic, the British Society of Gastroenterology guidelines emphasize that unexplained iron deficiency in adults warrants consideration of GI investigation due to malignancy risk, though this is most urgent when anemia is present 3

• For this non-anemic patient with mild iron deficiency: Initial trial of oral iron with close monitoring is reasonable 3, 1
• Bidirectional endoscopy (gastroscopy and colonoscopy) becomes indicated if:
  • No response to oral iron after 8-10 weeks despite adequate compliance 3, 1
  • Ferritin continues to decline despite supplementation 3
  • Patient develops anemia 3
  • Age >50 years with new-onset iron deficiency 4, 5
  • Any concerning GI symptoms develop 3

Dietary Optimization

• Emphasize heme iron sources (red meat, poultry, seafood) which have superior bioavailability 1
• Include non-heme sources (legumes, fortified cereals, dark leafy greens) with vitamin C-rich foods 1
• Separate calcium-rich foods from iron-rich meals by at least 2 hours 1
• Limit tea and coffee consumption around mealtimes 1

Critical Pitfalls to Avoid

• Do not discontinue iron therapy once symptoms improve—treatment must continue until ferritin reaches 50-100 μg/L to prevent relapse 1
• Do not assume heterozygous HFE variants explain the low ferritin—these variants do not cause iron deficiency and another etiology must be sought 3
• Do not delay investigation if ferritin continues declining despite treatment—this suggests ongoing blood loss or malabsorption requiring identification 3, 1
• Do not over-supplement beyond target ferritin levels, as this can lead to iron overload complications 1

When to Consider Intravenous Iron

IV iron is not currently indicated but should be considered if 1, 2:

• Oral iron intolerance develops
• Malabsorption disorder is identified (celiac disease, post-bariatric surgery)
• Inadequate response to oral iron despite compliance
• Need for rapid iron repletion emerges