eMedicine Specialties > Pediatrics: General Medicine > Hematology

Anemia, Chronic: Differential Diagnoses & Workup

Author: Susumu Inoue, MD, Professor of Pediatrics and Human Development, Michigan State University College of Human Medicine; Clinical Professor of Pediatrics, Wayne State University School of Medicine; Director of Pediatric Hematology/Oncology, Associate Director of Pediatric Education, Department of Pediatrics, Hurley Medical Center
Coauthor(s): John T Truman, MD, MPH, Professor of Clinical Pediatrics, Columbia University; Deputy Chair, Department of Pediatrics, Section of Hematology-Oncology, Babies and Children's Hospital of New York; Margaret T Lee, MD, Assistant Professor, Department of Pediatrics, Division of Pediatric Hematology, Children's Hospital of New York, Columbia University
Contributor Information and Disclosures

Updated: Dec 8, 2008

Differential Diagnoses

Other Problems to Be Considered

Acquired immunodeficiency syndrome (AIDS)
Congenital dyserythropoietic anemia
Diamond-Blackfan anemia
Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency
Hemophagocytic lymphohistiocytosis (HLH), congenital or acquired
Nutritional iron deficiency
Paroxysmal nocturnal hemoglobinuria
Pure red cell aplasia
Rheumatoid arthritis
Sideroblastic anemia
Unstable hemoglobinopathies

Workup

Laboratory Studies

• To evaluate anemia, obtain initial laboratory tests, including CBC count, reticulocyte count (most useful), and a review of the peripheral smear.
  • Base interpretation of the hemoglobin and hematocrit levels on the reference range for the specific age group. Some laboratories provide only a uniform reference range for the entire pediatric age group and not for specific age groups. Interpret this carefully to avoid misdiagnosis. Hemoglobin and hematocrit levels can be used interchangeably depending on professional preference and familiarity. Essentially, the hematocrit level is 3 times the hemoglobin value.
  • Red cell indices are quite informative, particularly mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and red cell distribution width (RDW).
    • Note that reference ranges for these parameters also vary with age. Because of this, the author suggests using the MCV cut-off point for patients aged 70 years or older in patients aged 7 years or younger (eg, MCV <72 is abnormal for patient aged 2 y). 
    • A high RDW (eg, ³ 19-20) with microcytic picture is most often indicative of iron deficiency anemia in pediatric population. The RDW is also very high in anemia with reticulocytosis, including sickle cell disease.
    • Macrocytosis suggests folate/vitamin B-12 deficiency; however, nutritional deficiencies of these vitamins are rare. 
    • Note that in newborns, MCV is physiologically in the range of 120-102. Beyond the immediate newborn period, MCV exceeding 98 is very uncommon in children; if the volume exceeds 98, it usually indicates a serious hematological problem, such as myelodysplastic syndrome, leukemia, aplastic anemia, Diamond-Blackfan anemia, or metabolic disorder.
    • In most, but not all cases of hereditary spherocytosis (HS), the MCHC exceeds the upper limit of the reference range.
  • Reticulocytes are immature nonnucleated RBCs that indicate active erythropoiesis.
    • The relative reticulocyte count is useful in determining whether anemia is caused by decreased production, increased destruction, or loss of RBCs. An elevated number of reticulocytes is (eventually) observed in individuals with anemia caused by hemolysis or blood loss; note that the absence of reticulocytosis may simply reflect a lag in the response to the acute onset of anemia.
    • The term reticulocyte count is often inaccurately used to refer to the percentage of reticulocytes, a value that must be interpreted in light of the degree of anemia. Thus, a finding of 2-3% reticulocytes (vs the reference value of approximately 1%) in a patient in whom the hemoglobin level is only one third to one half of reference range does not indicate a reticulocyte response. Some clinicians prefer to use either the absolute number of reticulocytes/μL of blood or a reticulocyte percentage that is corrected for the degree of anemia. The corrected reticulocyte count equals (patient hematocrit)/(reference range hematocrit times the percentage reticulocyte count).
  • Examination of the peripheral smear is particularly helpful in normocytic anemia. The red cell morphology itself is quite often diagnostic. The following are examples of abnormal cell morphology in normocytic picture:
    • Schistocytes or fragmented cells (microangiopathic hemolytic anemia), as in Media file 5
    • Spherocytes (hereditary spherocytosis, autoimmune hemolytic anemia, ABO hemolytic anemia in newborns), as in Media file 2
    • Ghost, bite, or helmet cells (glucose-6-phosphate dehydrogenase [G-6-PD]), as in Media file 1
    • Sickle-shaped cells (sickle cell disease), as in Media file 4 
    • Target cells (hemoglobin C, liver disease), as in Media file 3
    • Stippled RBCs, basophilic stippling (in all conditions with increased reticulocyte count and in lead poisoning and 5' nucleotides deficiency), as in Media file 6
    • Increased polychromasia (reticulocytosis)
  • Normal RBC morphology does not exclude hemolysis.
• Additional laboratory tests that may be indicated in the diagnosis and treatment of patients with acute anemia include the following:
  • Bilirubin level, lactate dehydrogenase (LDH) level (hemolytic anemia), and serum haptoglobulin level (decreased or none in chronic hemolytic anemia)
  • Direct antiglobulin (DAT) or Coombs test (autoimmune hemolytic anemia)
  • Hemoglobin electrophoresis (hemoglobinopathies)
  • Hemoglobin A2 quantitation (β-thalassemia trait, increased above 3.5%)
  • Red cell enzyme studies (eg, G-6-PD, pyruvate kinase), osmotic fragility (spherocytosis) (Note that G-6-P D deficient red cells may show normal G-6-PD screening result in the presence of reticulocytosis; thus, actual enzyme quantitation is strongly recommended. Normal enzyme level in the presence of reticulocytosis indicates deficiency).
  • Iron, total iron-binding capacity, and ferritin levels (iron deficiency anemia); soluble (serum) transferrin receptor (differentiation of iron deficiency anemia [increased] from anemia of chronic disease [normal]); free erythrocyte protoporphyrin (FEP) or zinc erythrocyte protoporphyrin (for partially treated iron-deficiency anemia), increased in the presence of normal serum iron)
  • Stool for occult blood (Examine at least 3 specimens. In the presence of demonstrated intestinal blood loss, any given stool specimen finding may be negative; thus, multiple specimens are required before one can conclude a negative finding.)
  • Folate and vitamin B-12 levels (macrocytic/megaloblastic anemia)
  • Blood typing and crossmatching to assess possible isoimmune anemia in a neonate and to prepare for transfusion
  • Bone marrow aspiration and biopsy (to rule out leukemia, aplastic anemia, tumor cells in the marrow such as neuroblastoma, megaloblastosis, marrow dysplasia, hemophagocytosis, and detection of absence of one cell line due to pure red cell aplasia or parvovirus infection)
  • Viral titers (eg, Epstein-Barr virus, cytomegalovirus, parvovirus B19)
  • BUN/creatinine levels to assess renal function
  • Thyroxine (T₄)/thyroid-stimulating hormone (TSH) levels to exclude hypothyroidism

Imaging Studies

• Exclude impending high-output congestive heart failure using chest radiography and ultrasonography. If hemolysis is suspected, look for increased marrow activity using findings on skull films and films of the hands and wrists. 
• Detecting a large spleen using ultrasonography or CT scanning for suspected hypersplenism is not recommended. If a thorough physical examination does not detect palpable spleen, hypersplenism is not a likely diagnosis.
• Ultrasonography of the gallbladder for the presence of gallstones in patients with chronic hemolytic anemia may be valuable if the patient has recurrent abdominal pain. Abdominal pain due to gallstones in children is not always in the right upper quadrant. The author has received reports of left upper quadrant pain in children with gallstones that subsided after cholecystectomy.

Other Tests

• Exclude impending high-output congestive heart failure using ECG.

Procedures

• Specimens from bone marrow aspiration and biopsy are often essential in helping characterize overall cellularity, presence or absence of tumor cells, morphology and maturation of red cell precursors, and presence or absence of stainable iron.

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