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

Approach to Low Hemoglobin, Elevated Ferritin, and Elevated ALP

The combination of anemia with elevated ferritin and elevated alkaline phosphatase most commonly indicates anemia of chronic disease (ACD) or anemia of inflammation, and your primary focus should be identifying the underlying inflammatory, infectious, or malignant condition driving this pattern rather than treating the anemia itself. 1

Initial Diagnostic Framework

The elevated ferritin in the setting of anemia signals either iron overload with anemia or, more commonly, an acute phase response where ferritin rises due to inflammation rather than reflecting true iron stores 1, 2. The concurrent elevation of alkaline phosphatase adds another layer, suggesting possible hepatobiliary involvement, bone disease, or systemic inflammation.

Key Laboratory Assessment

Obtain the following tests immediately to differentiate the underlying cause:

• Transferrin saturation (TSAT): This is the critical discriminator 1

  • TSAT <20% with ferritin >300 ng/mL strongly suggests anemia of inflammation 1
  • TSAT >50% suggests iron overload disorders despite anemia 1
  • Normal TSAT (20-50%) requires further investigation

• C-reactive protein (CRP): Elevated CRP confirms active inflammation and supports ACD diagnosis 1

• Mean corpuscular volume (MCV): Helps classify the anemia type 1

  • Microcytic (low MCV): Consider iron-restricted erythropoiesis, genetic iron disorders, or thalassemia
  • Normocytic: More typical of ACD or mixed disorders
  • Macrocytic: Suggests B12/folate deficiency or other causes

• Reticulocyte count: Low or inappropriately normal reticulocytes indicate inadequate bone marrow response, consistent with ACD or deficiency states 1

Differential Diagnosis Based on Pattern

Pattern 1: Low TSAT (<20%) + High Ferritin (>300 ng/mL) + Elevated ALP

This pattern indicates anemia of chronic disease/inflammation. 1

Search for these underlying conditions:

• Inflammatory bowel disease: The elevated ALP may reflect hepatobiliary complications or bone disease from malabsorption 1
• Chronic infections: Including occult abscesses, endocarditis, or chronic viral hepatitis
• Malignancy: Particularly hematologic malignancies or metastatic disease to liver/bone (ALP source) 2, 3
• Autoimmune diseases: Rheumatoid arthritis, systemic lupus erythematosus
• Chronic kidney disease: Part of cardio-renal anemia syndrome 1
• Congestive heart failure: Especially if other cardiac symptoms present 1
• Chronic liver disease: Alcoholic liver disease commonly causes this triad 2, 4

The elevated ALP specifically suggests:

• Hepatobiliary disease (check GGT to confirm hepatic source)
• Bone disease (check bone-specific ALP or imaging)
• Infiltrative liver disease from malignancy or infection

Pattern 2: High TSAT (>50%) + High Ferritin + Anemia + Elevated ALP

This paradoxical pattern suggests genetic iron metabolism disorders with true iron overload despite anemia. 1

Consider these rare but important diagnoses:

• Ferroportin disease (loss-of-function mutations): Anemia develops during phlebotomy treatment despite elevated ferritin 1

  • Autosomal dominant inheritance
  • Iron accumulates in reticuloendothelial system
  • Genetic testing for SLC40A1 mutations indicated

• Aceruloplasminemia: Very low/absent ceruloplasmin with low serum copper and iron, high ferritin, and systemic iron loading 1

  • Look for diabetes, neurodegeneration, retinal degeneration
  • MRI shows iron accumulation in liver, pancreas, brain
  • Genetic testing for CP mutations

• Hypotransferrinemia: Low transferrin with high ferritin and systemic iron overload 1

  • Presents in early life with severe anemia
  • Genetic testing for TF gene mutations

• Hemosiderosis from chronic alcohol use: Distinguished from genetic hemochromatosis by history and normal genetic testing 4

Pattern 3: Normal TSAT + High Ferritin + Anemia + Elevated ALP

This intermediate pattern requires investigation for:

• Metabolic syndrome: Common cause of hyperferritinemia without true iron overload 2, 3
• Chronic liver disease with cytolysis: Check ALT/AST 2
• Mixed iron deficiency and inflammation: Particularly in inflammatory bowel disease 1
• Hematologic disorders: Myelodysplastic syndromes, chronic hemolytic anemias 2

Critical Next Steps

If Inflammatory Pattern (Low TSAT, High Ferritin)

1. Do NOT give iron supplementation initially - this can worsen outcomes in active inflammation and will not correct the anemia 1

2. Identify and treat the underlying inflammatory condition - this is the primary intervention 1

3. Consider iron therapy only after:

   • Inflammation is controlled
   • True iron deficiency is confirmed (ferritin <100 ng/mL after inflammation resolves) 1
   • In specific conditions like heart failure or IBD where evidence supports benefit despite inflammation 1

4. For source of elevated ALP:

   • Obtain liver imaging (ultrasound or CT) if hepatic source suspected
   • Check bone-specific ALP or bone scan if bone source suspected
   • Evaluate for infiltrative disease if no clear source

If Iron Overload Pattern (High TSAT, High Ferritin)

1. Obtain MRI with iron quantification to assess hepatic iron content - this is essential to guide therapy 1, 2, 3

2. Genetic testing for:

   • HFE mutations (hemochromatosis) - though typically doesn't present with anemia
   • SLC40A1 (ferroportin disease) if anemia with iron overload 1
   • CP gene (aceruloplasminemia) if neurologic symptoms present 1

3. Treatment depends on diagnosis:

   • Ferroportin disease: Phlebotomy with extended intervals if anemia develops; consider EPO 1
   • Aceruloplasminemia: Iron chelation therapy, NOT phlebotomy 1
   • Avoid aggressive iron removal if anemia worsens 1

Common Pitfalls to Avoid

Do not assume elevated ferritin always means iron overload - in >40% of cases, multiple etiologies coexist, and ferritin elevation is often inflammatory rather than reflecting true iron stores 2, 3

Do not start empiric iron supplementation without determining TSAT - giving iron in ACD can cause harm without benefit 1

Do not ignore the elevated ALP - this provides crucial diagnostic information about liver, bone, or infiltrative disease that may be the primary pathology 2

Do not perform phlebotomy in patients with anemia and elevated ferritin without genetic confirmation of an iron overload disorder - this can worsen anemia in ferroportin disease or other conditions 1

Monitor ferritin levels carefully if iron supplementation is given - levels should not exceed 500 ng/mL to avoid toxicity, especially in children and adolescents 1