Anemia of chronic disease differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Shyam Patel [2]Associate Editor(s)-in-Chief: Omer Kamal, M.D.[3]

Overview

The most important differential is whether the patient has ACD alone or ACD with ongoing iron deficiency anemia (ACD/IDA). The following parameters will distinguish the two: Soluble transferrin receptor levels (sTfR) and/or the sTfR-ferritin index sTfR and the sTfR-ferritin index are normal in uncomplicated ACD, while both are elevated when IDA is also. Percentage of hypochromic red cells and reticulocyte hemoglobin may help.

Differential Diagnosis

Concomitant iron deficiency

The most important differential is whether the patient has ACD alone or ACD with ongoing iron deficiency anemia (ACD/IDA). The following parameters will distinguish the two:

●Soluble transferrin receptor levels (sTfR) and/or the sTfR-ferritin index sTfR and the sTfR-ferritin index are normal in uncomplicated ACD, while both are elevated when IDA is also present[1]

●Percentage of hypochromic red cells and reticulocyte hemoglobin may help[2][3]

Bone marrow examination in n difficult cases the diagnosis can often be established by bone marrow examination. Findings in the most common disorders include:

Myelodysplastic syndromes

Single or multi-lineage dysplastic changes with or without increased number of sideroblasts, including ring forms, are commonly seen in patients with myelodysplasia

Sideroblastic anemias

Presence of ring sideroblasts on bone marrow examination

●Serum erythropoietin (EPO) levels lower in ACD than in patients with IDA and comparable degrees of anemia[4]

●Oral iron supplementation for four to six weeks may help in the differentiation between ACD and ACD/IDA

Endocrine disorders

Hyperthyroidism, hypothyroidism, panhypopituitarism, and primary and secondary hyperparathyroidism may also present with a normocytic, normochromic hypoproliferative anemia.

Miscellaneous

IDA, thalassemia, sideroblastic anemias, and the sideroblastic variants of the myelodysplastic syndrome[5]

Anemia must be differentiated based on different laboratory findings including mean cell volume (MCV), reticulocytosis, and hemolysis.

To review the differential diagnosis of anemia, see below table.

To review the differential diagnosis of microcytic anemia, click here.

To review the differential diagnosis of normocytic anemia, click here.

To review the differential diagnosis of macrocytic anemia, click here.

To review the differential diagnosis of hypochromic anemia, click here.

To review the differential diagnosis of normochromic anemia, click here.

To review the differential diagnosis of anisochromic anemia, click here.

To review the differential diagnosis of hemolytic anemia, click here.

To review the differential diagnosis of anemia with intrinsic hemolysis, click here.

To review the differential diagnosis of anemia with extrinsic hemolysis, click here.

To review the differential diagnosis of anemia with low reticulocytosis, click here.

To review the differential diagnosis of anemia with normal reticulocytosis, click here.

To review the differential diagnosis of anemia with high reticulocytosis, click here.

Disease Genetics Clinical manifestation Lab findings
History Symptoms Signs Hemolysis Intrinsic/

Extrinsic

Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Iron studies Specific finding on blood smear
Serum iron Serum Tfr level Transferrin or TIBC Ferritin Transferrin saturation
Iron deficiency anemia[6] Hypochromic Microcytic Nl or ↓ Nl Nl ↓↓↓
Iron deficiency anemia (early phase)[7] Normochromic Normocytic Nl Nl
Lead poisoning[8]
  • House painted with chipped paint
Hypochromic Microcytic Nl Nl or ↓ Nl Nl Nl to ↓ Nl Nl Nl to ↓
  • RBCs retain aggregates of rRNA
  • Basophilic stippling
Sideroblastic anemia[9] Hypochromic Microcytic Nl Nl or ↓ Nl Nl Nl Nl to ↓
Disease Genetics History Symptoms Signs Hemolysis Intrinsic/

Extrinsic

Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Serum iron Serum Tfr level IBC Ferritin Transferrin saturation Specific finding on blood smear
Anemia of chronic disease[10] Hypochromic Microcytic Nl Nl or ↓ Nl Nl NA
Thalassemia[11] α-thalassemia
  • α- globin gene deletions
  • Cis deletions
  • Trans deletions

β-thalassemia

α-thalassemia

β-thalassemia

Hypochromic Microcytic Nl
  • Thalassemia trait: Nl or ↓
  • Thalassemia Syndromes: ↑
Nl Nl Nl to ↑ Nl Nl Nl to ↑
G6PD deficiency[12]
  • History of using
+ Intrinsic Normochromic Normocytic ↑ but usually causes resolution within 4-7 days Nl to ↑ Nl
Pyruvate kinase deficiency[13] + Intrinsic Normochromic Normocytic Nl Nl Nl
Disease Genetics History Symptoms Signs Hemolysis Intrinsic/

Extrinsic

Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Serum iron Serum Tfr level IBC Ferritin Transferrin saturation Specific finding on blood smear
Sickle cell anemia[14] + Intrinsic Normochromic Normocytic Nl or moderately ↑ Nl Nl Nl or moderately ↑ Nl
HbC disease[15]
  • Glutamic acid–to-lysine mutation in β-globin
+ Intrinsic Normochromic Normocytic Nl Nl Nl Nl
Paroxysmal nocturnal hemoglobinuria[16][17] + Intrinsic Normochromic Normocytic Nl Nl NA
Hereditary spherocytosis[18] + Intrinsic Normochromic Normocytic Nl Nl Nl
  • Small, round RBCs with less surface area and no central pallor
Disease Genetics History Symptoms Signs Hemolysis Intrinsic/

Extrinsic

Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Serum iron Serum Tfr level IBC Ferritin Transferrin saturation Specific finding on blood smear
Microangiopathic hemolytic anemia[19][20] Associated with + Extrinsic Normochromic Normocytic Nl Nl
  • Helmet cells
Macroangiopathic hemolytic anemia[21] Associated with + Extrinsic Normochromic Normocytic Nl Nl
Autoimmune hemolytic anemia[22] Associated with:
  • Painful, blue fingers and toes with cold weather
+ Extrinsic Normochromic Normocytic Nl Nl
  • RBC agglutination
Aplastic anemia[23]
  • Symptoms based on underlying condition
Normochromic Normocytic Nl Nl Nl
Disease Genetics History Symptoms Signs Hemolysis Intrinsic/

Extrinsic

Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Serum iron Serum Tfr level IBC Ferritin Transferrin saturation Specific finding on blood smear
Folate deficiency[24]
  • Impaired DNA synthesis
Anisochromic Macrocytic Nl Nl
Vitamin B12 deficiency[25] Anisochromic Macrocytic Nl Nl
Orotic aciduria[26]
  • Neurological manifestation
Anisochromic Macrocytic Nl Nl NA
Fanconi anemia[27]
  • Significant for bilateral short thumbs
Anisochromic Macrocytic Nl Nl
Disease Genetics History Symptoms Signs Hemolysis Intrinsic/

Extrinsic

Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Serum iron Serum Tfr level IBC Ferritin Transferrin saturation Specific finding on blood smear
Diamond-Blackfan anemia[28] Mutations in:
  • RPL5
  • RPL11
  • RPL35A
  • RPS7
  • RPS10
  • RPS17
  • RPS19
  • RPS24
  • RPS26
Anisochromic Macrocytic Nl Nl Nl NA
Infections[29] Associated with + Extrinsic Normochromic Normocytic Nl Nl Nl
Chronic kidney disease[30] Normochromic Normocytic Nl/↑ Nl Nl
Liver disease[31]
  • Hepatitis
  • Binge drinking
  • Gall bladder disease
Anisochromic Macrocytic Nl Nl
Alcoholism[32] Anisochromic Macrocytic Nl Nl
Disease Genetics History Symptoms Signs Hemolysis Intrinsic/

Extrinsic

Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Serum iron Serum Tfr level IBC Ferritin Transferrin saturation Specific finding on blood smear

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