Clinical Scenario

You are seeing a nine month old male for a regular checkup. He has a hematocrit of 28% on a spun specimen in your office. How would you evaluate this patient for anemia?

Definition of Anemia

You have correctly identified this patient as being anemic. Anemia is generally defined as a hemoglobin (Hb) or hematocrit (Hct) that is more than two standard deviations below the mean for the reference population. When evaluating anemia it is important to consider the normal reference range given the child’s age, gender, and race (see table below).

Hemoglobin, hematocrit, red blood cells, mean corpuscular volume, and white blood cells in children 1-14 years of age, by age group and sex:

* The 95% confidence interval (+/- 2 SD) defines the normal range, and corresponds to the 2.5th through 97.5th percentiles.

History

1.     Severity and initiation of symptoms

a.     Lethargy

b.     Tachycardia

c.     Pallor

d.     Irritability

e.     Poor oral intake

f.      No symptoms commonly seen in chronic anemia whereas acute anemia tends to be more symptomatic

2.     Evidence of hemolytic episodes

a.     Changes in urine color

b.     Scleral icterus

c.     Jaundice

d.     Hemolytic episodes only in male family members may suggest X-linked disorder (e.g. G6PD deficiency)

3.     Prior therapy or anemic episodes

a.     Prior anemic episodes, duration, etiology, and resolution

b.     Prior therapy for anemia (e.g. failed iron therapy)

4.     Blood Loss

a.     GI bleeding: changes in stool color, blood in stools, bowel symptoms

b.     Menstrual losses: duration of periods, flow, and saturation of tampons or pads

c.     Severe epistaxis

d.     If significant blood loss, probe family history for inflammatory bowel disease, polyps, colorectal cancer, hereditary hemorrhagic telangiectasia, von Willebrand disease, platelet disorders, and hemophilia

5.     Underlying medical conditions

a.     Chronic underlying infectious or inflammatory conditions

b.     Recent illnesses

c.     Travel to/from areas of endemic infection (e.g. malaria)

6.     Prior drug or toxin exposure

a.     Environmental toxin exposure (e.g. well water containing nitrates)

b.     Homeopathic or herbal medications

c.     Risk for lead exposure: housing, paint, cooking materials, poorly glazed ceramic pots

7.     Diet

a.     Iron intake

                                               i.     Formula (formulas with iron have approximately 12 mg/L and should be continued for 12 months)

                                             ii.     Milk intake and time of discontinuation

1.     Breast milk is an adequate source of iron for 6 months without any supplements

2.     Only about 10% of iron in whole milk is available for absorption and it may cause GI bleeding and loss of iron

                                            iii.     Cereals, greens, and meat (good source of iron for older children)

                                            iv.     Ascorbic acid (enhances the absorption of dietary iron)

b.     B12 / folate intake (less important than iron)

c.     Pica: eating dirt, paint chips, and any unusual substances (often associated with iron deficiency)

8.     Birth History

1. Gestational age at birth
1. Preterm infants have less iron stores and they grow faster requiring their diets to be supplemented with iron, whereas full term infants have enough iron stores for 4 months
2. Preterm infants may have iron or vitamin E deficiencies resulting in anemia
2. Significant loss of blood at birth (may affect the amount of iron stores)
3. History of exchange or intrauterine transfusion
4. Jaundice or need for phototherapy (may suggest inherited hemolytic anemia)
5. Microcytosis at birth (may suggest chronic intrauterine blood loss and alpha thalassemia)

9. Growth / developmental history
1. Normal height and weight gain usually eliminate chronic disease as etiology of anemia
2. Loss of milestones or developmental delay (in infant with megaloblastic anemia, may suggest defect of B12 or folate pathways)
10. Family History
1. History of anemias
2. Splenectomies
3. Sickle cell disease
4. G6PD deficiency
5. Cholelithiasis
6. Transfusions
11. Race / ethnicity
1. Mediterranean and Southeast Asian: thalassemias
2. Black and Hispanic: Hb S and C
3. Sephardic Jews, Filipinos, Greeks, and Kurds: G6PD deficiency

Physical Exam

1. GEN:   Evidence of chronic disease
2. HEENT: Conjunctival pallor, glossitis (associated with B12 and iron deficiency), frontal bossing (seen in thalassemias)
3. CV: Heart rate and presence of murmur
4. ABD: Hepatomegaly (malignancies, extrameduallary hematopoesis, chronic diseases), splenomegaly (hemolytic anemias, ALL, lymphomas, extrameduallry hematopoiesis)
5. LYMPH: Significant adenopathy (leukemias and lymphomas, chronic diseases, HIV)
6. SKIN: Petechiae, purpura, jaundice, hemangiomas
7. EXTR: Radial anomalies (associated with congenital anemias, e.g. Fanconi's anemia)

Therapeutic Trial of Iron

If the physical exam, history, and diet history are suggestive of iron deficiency, a therapeutic trial of iron (6 mg/kg/day) is advisable before embarking on an extensive laboratory evaluation. The hematocrit should be rechecked in one month.

If there is a rise in the hematocrit of at least three percentage points (or Hgb rise of 1 g/dL), the diagnosis is iron deficiency and the patient should be treated for two more months with iron. Diet advice must be given to the parents.

If there is not a significant rise in the hematocrit, further evaluation is necessary:

Initial Laboratory Studies

1. Complete blood count (CBC) with differential
1. Mean corpuscular volume (MCV): micro- vs. normo- vs. macrocytosis
2. Red cell distribution width (RDW): evaluates anisocytosis (normal is 11.5-14.5), usually increased with Fe deficiency
3. Leukopenia, neutropenia, and/or thrombocytopenia may signify abnormal bone marrow function or increased peripheral destruction of blood cells
2. Reticulocyte count: indication of bone marrow erythropoietic activity
3. Blood cell smear
1. RBC size: microcytosis vs. macrocytosis
2. Central pallor: Increased central pallor (iron deficiency and thalassemia) or no central pallor (spherocytes  and reticulocytes)
3. Fragmented cells (microangiopathic process)
4. Sickle cells (sickle cell disease)
5. Elliptocytes (congenital elliptocytosis)
6. Target cells (thalassemia, in liver disease, and post-splenectomy)
7. Bite cells (Heinz body hemolytic anemia)

The findings of initial testing will guide additional workup.

References

1. Bain B. Diagnosis from the Blood Smear. NEJM 353;5 Pg 498 August 4, 2005.
2. Crocetti M et al.  Transient erythropenia of childhood: Listening for the quiet anemia. Contemporary Pediatrics April 2002.
3. [Table] Hollowell JG et al. Hematological and iron-related analytes-reference data for persons aged 1 year and over: United States, 1988-94. Vital Health Stat 2005; 11:1.
4. Oski F. Iron Defiency in Infancy and Childhood. NEJM Vol. 329 No. 3 190-193 1993.
5. Robins EB et al. Hematologic reference values for African American children and adolescents. Am J Hematol. 2007;82(7):611.
6. Sackey K. Hemolytic Anemia: Part 1. Pediatrics in Review. 1999; 20:152-159.
7. Sackey K. Hemolytic Anemia: Part 2. Pediatrics in Review. 1999; 20:204-208.
8. Segel G et al. Managing Anemia in a Pediatric Office Practice Part 1. Pediatrics in Reiview. March 2002.
9. Segel G et al. Managing Anemia in a Pediatric Office Practice Part 2. Pediatrics in Review. April 2002.
10. Sandoval C et al. Approach to the child with anemia. UpToDate.com. Last updated Feb  2011. Accessed May 2011.
11. Shah S et al. Hereditary Spherocytosis.  Pediatrics in Review. May 2004.