What is the management approach for a patient with anemia (low hemoglobin), elevated ferritin, and elevated alkaline phosphatase (ALP)?

Management of Low Hemoglobin with Elevated Ferritin and Elevated ALP

Do not give iron supplementation when ferritin is elevated and transferrin saturation is adequate, as this indicates iron overload or anemia of chronic disease, not iron deficiency. 1

Initial Diagnostic Approach

The combination of anemia with elevated ferritin and elevated ALP requires systematic evaluation to distinguish between iron overload disorders, chronic disease, and genetic iron metabolism defects.

First-Line Laboratory Assessment

• Calculate transferrin saturation (TSAT) immediately - this is the critical discriminating test 1

  • TSAT >45-50% with elevated ferritin suggests primary iron overload (hemochromatosis, ferroportin disease) 2, 3
  • TSAT >20% with ferritin >100 ng/mL indicates functional iron deficiency from chronic disease, NOT absolute iron deficiency 1
  • Low TSAT with elevated ferritin suggests anemia of chronic disease or genetic disorders like IRIDA 2

• Assess the MCV (mean corpuscular volume) to categorize the anemia 2

  • Microcytic (MCV <80 fL): Consider genetic iron metabolism disorders, thalassemia, or chronic disease 2
  • Normocytic: Consider ferroportin disease, chronic kidney disease, or malignancy 2, 4

• Measure total iron-binding capacity (TIBC) 2

  • Low TIBC suggests chronic inflammation, iron overload, or liver disease 1
  • High TIBC with low TSAT suggests true iron deficiency (uncommon with elevated ferritin) 2

Common Clinical Scenarios

Scenario 1: Elevated TSAT (>45%) + Elevated Ferritin + Anemia

This pattern suggests primary iron overload with anemia, most commonly ferroportin disease (loss-of-function mutations) 2:

• Screen for SLC40A1 mutations (ferroportin gene) in first-degree relatives 2
• Initiate phlebotomy therapy as primary treatment 2
• If anemia worsens during phlebotomy despite elevated ferritin, extend phlebotomy intervals and consider EPO therapy 2, 1
• Monitor ferritin to keep <500 μg/L to avoid long-term toxicity, especially in younger patients 2

Scenario 2: Low/Normal TSAT + Elevated Ferritin + Microcytic Anemia

This pattern suggests genetic iron metabolism disorders or iron-refractory iron deficiency anemia (IRIDA) 2:

• Consider TMPRSS6 gene testing for IRIDA if oral iron has been ineffective 2
• Exclude common causes first: thalassemia, hemoglobinopathies, severe anemia of chronic disease 2
• Check for celiac disease with tissue transglutaminase (tTG) antibody, as ~5% of IDA patients have celiac disease 2
• Treatment for confirmed IRIDA: Intravenous iron (iron sucrose or iron gluconate) is preferred over oral iron 2
  • Target ferritin <500 mg/L to avoid iron overload 2
  • Complete normalization of hemoglobin is rarely achieved 2

Scenario 3: Elevated Ferritin + Anemia + Elevated ALP (Liver Involvement)

The elevated ALP suggests hepatic involvement or systemic disease 3, 5:

• Most common causes of hyperferritinemia: alcoholism, inflammatory syndrome, cytolysis, metabolic syndrome, and malignancy 3, 4
• Obtain liver MRI with iron quantification (T2/T2 relaxometry)* if ferritin is very high (>1000 μg/L) or rising, to assess hepatic iron overload 5
• Screen for malignancy - this is the most frequent cause of markedly elevated ferritin (>1000 μg/L) in tertiary care settings 4
• Check for hemolysis markers if ALP is disproportionately elevated: LDH, haptoglobin, indirect bilirubin 6, 7

Treatment Algorithm Based on Iron Status

If Iron Overload is Confirmed (Ferritin ≥1,000 ng/mL)

• Iron chelation with deferasirox is indicated for 1:

  • Ferritin ≥1,000 ng/mL with transfusion requirement ≥2 units/month for >1 year
  • Need to preserve organ function
  • Stem cell transplant candidates (even at lower ferritin levels to reduce transplant mortality) 1

• Monitor regularly: serum ferritin, CBC, liver and renal function, TSAT 1

• Stop chelation if ferritin falls below 500 ng/mL unless specific indications exist 1

If Anemia of Chronic Disease is Suspected

• Investigate underlying cause: chronic kidney disease, myelodysplastic syndrome, inflammatory conditions, malignancy 1, 4
• Do NOT give iron supplementation when TSAT is adequate (>20%) and ferritin is elevated 1
• Treat the underlying condition rather than the iron parameters 3

Critical Pitfalls to Avoid

• Never give oral or IV iron based solely on low hemoglobin when ferritin is elevated and TSAT is adequate - this causes harmful iron overload 1
• Do not start chelation prematurely (ferritin <1,000 ng/mL) unless specific high-risk indications exist 1
• Do not assess iron status during acute illness or crisis - ferritin rises dramatically with tissue damage and does not reflect true iron stores 6
• Do not assume a single etiology - more than 40% of hyperferritinemia cases have multiple contributing causes 3
• Do not skip genetic testing when conventional tests fail to identify the cause, especially in microcytic anemia with family history 2, 7

When to Refer

• Refer to hematology if genetic iron disorder is suspected (IRIDA, ferroportin disease, sideroblastic anemia) 2
• Refer to clinical genetics for complex genotype-phenotype correlations in IRIDA or ferroportin disease 2
• Consider hepatology referral if significant hepatic iron overload is demonstrated on MRI 5