What Causes Anemia?

Patient Presentation
An 8-year-old female with an underlying genetic syndrome presented with some fatigue, cough and fever for 3 days. The patient had no bruising or bleeding symptoms. The past medical history showed her to eat a variety of pureed feeds and receive overnight continuous feeds through a gastrostomy tube. The liquid nutritional supplement did have iron in it. The family history was negative for any hematological problems including anemia. The review of systems was negative.

The pertinent physical exam showed a non-verbal female who looked mildly ill with a temperature of 38.0°C, heart rate of 96 beats/minute and respiratory rate of 24.
She was in her wheelchair. HEENT showed pale, non-icteric conjunctiva, mild rhinorrhea, with normal pharynx and ears. She did not have increased work of breathing and she had transmitted upper airway noises. Her abdomen was soft, non-tender without adenopathy and her G-tube area had normal skin. Rectal examination was negative for occult blood. She had no skin lesions. The laboratory evaluation included a complete blood count which showed a hemoglobin of 7.8 g/dL, MCV of 71 fl, and with normal platelets, white blood cells and cell subtypes. The peripheral smear showed small pale cells without abnormal shape. The reticulocyte count was low. Iron studies completed later were consistent with iron deficiency anemia. Lead and thyroid testing were negative.

The work-up included a chest radiograph that was negative. An ultrasound examination of her abdomen to evaluate for occult masses or other pathology was also negative. A review of her medications did not show any that caused bone marrow suppression or hemolysis.

The diagnosis of iron deficiency anemia and an upper respiratory tract infection were made. It was unclear why she had the iron deficiency anemia because it appeared that she should have had adequate nutrition from her oral and gastrostomy feedings. Iron supplementation was begun and a dietician reviewed her diet but did not recommend any additional changes. The patient’s clinical course over the next month showed that her upper respiratory tract infection had improved, but she was somewhat less energetic than she usually was. Her repeat laboratory testing showed a hemoglobin of 9.6 g/dL and a reticulocyte count of 18%. Her other hematologic indices also improved. She continued to have no obvious bleeding symptoms. At that time the physician elected to continue to monitor her and felt that her anemia and fatigue were still most likely due to nutritional deficiency and would monitor her closely.

One of the most common problems in pediatrics is anemia. It is defined as “a lower than normal value for the related measurements of hemoglobin, hematocrit, and number of red blood cells”, usually 2 standard deviations below the normal for age. Normal hematological values change with age. For a discussion of which values are used click here.

The most common type of anemia in childhood is iron deficiency which is commonly caused by inadequate stores (e.g. premature infant), inadequate intake (e.g. poor nutrition) or blood loss (e.g. menses). Anemia screening is recommended at age 9-12 months, and for adolescent males and females during routine health examinations. As iron deficiency is the most common cause, often a trial of therapeutic iron (2-6 mg/kg/day of elemental iron) is started and then a complete blood count is rechecked ~ 1 month later. If iron deficiency is the cause then there should be an increase in the hemoglobin and hematocrit. If not, other causes must be sought. For a discussion of why anemias may not correct click here.

History is very important to help direct the evaluation and workup. A detailed dietary history including pica or lead ingestion can give clues to a possible dietary reason for the anemia, especially iron deficiency anemia. Blood loss history including trauma, bleeding or potential occult loss from the genitourinary tract are also very helpful. Bone marrow production problems (e.g. malignancy, infectious diseases) or hemolysis risks (e.g. sickle cell anemia) also must be looked for. Some causes have multiple etiologies such as a decreased red blood cell half life coupled with increased risk for hemolysis (e.g. sickle cell anemia).

Signs and symptoms of anemia include:

  • No symptoms
  • Developmental delay
  • Irritability
  • Heart failure
  • Lethargy and fatigue
  • Organomegaly – spleen, liver, lymph nodes
  • Pallor
  • Poor oral intake
  • Tachycardia
  • Signs of hemolysis – jaundice, paleness, dark urine
  • Stool color changes, blood in stool or urine
  • Weight loss

Review of the medical records for family history of anemia or hematopoietic diseases is very important along with reviewing any previous laboratory testing including neonatal screening. Sometimes much of the needed evaluation has already been previously completed for other reasons such as neonatal screening.

It is also important to evaluate all components of the complete blood count to look for other abnormalities such as platelet or white blood cell count problems. Other related cases can be found here: Lymphocytosis, Eosinophilia, Thrombocytosis, and Thrombocytopenia.

Learning Point
The differential diagnosis of anemia includes:

  • Nutritional
    • Iron deficiency
      • Poor nutrition – inadequate iron intake, abnormal eating patterns
      • Other nutrient deficiencies – folate, B12, riboflavin, Vitamin C, copper
      • Excessive milk intake
    • Lead toxicity
    • Malabsorption
    • Prematurity because of inadequate stores
  • Anemia of chronic disease
    • Autoimmune diseases
    • Liver disease
    • Hypothyroidism
  • Hematological
    • Hematopoietic problem
      • Congenital aplastic anemia
      • Fanconi
      • Blackfan-Diamond
      • Schwachman
      • Malignancy
      • Transient erythroblastopenia of childhood
      • Medication or toxin exposure – anticonvulsants, Zidovudine
      • Storage diseases – lipids, Langerhans cell histocystosis
    • Hemolysis
      • Congenital hemolytic anemia
        • Membrane defects
          • Elliptocytosis
          • Hereditary spherocytosis
        • Enzyme defects
          • G-6-PD deficiency
          • Pyruvate kinase deficiency
        • Hemoglobin problems
          • Sickle cell disease
          • Hemoglobin S or C or other hemoglobinopathies
          • Sideroblastic anemia
          • Thalassemia
        • Immune hemolytic anemia – Rh or ABO incompatibility, cold agglutinin, warm agglutinin
        • Microangiopathic hemolytic anemia – hemolytic uremia syndrome, Kasabach-Merritt syndrome
        • Hypersplenism
        • Liver disease
        • Renal disease
        • Telangectasia
        • Wilson disease
        • Mechanical – artificial heart valve
        • Medication or toxin exposure – anticonvulsants, Zidovudine, aluminum, lead
      • Infectious disease
        • Congenital infection
        • Bacteremia/Septicemia/Disseminated intravascular coagulation
        • Malaria
        • Viral
          • Common viral infections
          • Congenital infections
          • Hepatitis
    • Blood loss
      • Epistaxis
      • Cephalohematoma
      • Gastrointestinal – inflammatory bowel disease, polyps, varices, Meckel’s diverticulum
      • Menses
      • Trauma
        • Other bleeding problems such as hemophilia or platelet disorders
        • Twin-twin transfusion
        • Placental/umbilical bleeding
        • Pulmonary hemosiderosis
        • Hemorrhagic disease of the newborn
        • Urinary – paroxysmal nocturnal hemoglobinuria
    • Other
      • Dilutional
      • Excessive phlebotomy
      • Munchausen syndrome or Munchausen by proxy

Questions for Further Discussion
1. On a peripheral blood smear, what types of findings are helpful in determining an anemia’s cause?
2. Anemia is often classified by red blood cell size. What are some of the common causes of microcytic, normocytic or macrocytic anemias?
3. What are indications for a bone marrow evaluation in a child with anemia?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Anemia

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Sheldon SH, Levy HB. Pediatric Differential Diagnosis. Second Edition. Raven Press: New York. 1985:12-15.

Cohen PS. Anemia, in Pediatrics A Primary Care Approach, Berkowitz CD ed. W.B. Saunders Co. Philadelphia PA. 1996;230-34.

Engorn B, Flerlage J. The Harriet Lane Handbook. 20th Edit. Elsevier Saunders. 2015: 308.

Sandoval C. Approach to the Child with Anemia. UpToDate. (online resource) (rev. 6/4/2015, cited 2/25/17).

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital