Why is the Anemia Not Correcting?

Patient Presentation
A 9 month-old white male was admitted for respiratory syncytial virus bronchiolitis with an oxygen need. He responded to bronchodilators and oxygen and was discharged after two days.
During the hospitalization it was noticed that his hemoglobin was 10.9 mg/dL and mean corpuscular volume (MCV) was 64 fL (both low) on his admission complete blood count (CBC).
He had been breast fed and had iron containing foods begun at 5 months of age. He was born at 39 weeks and had no otherproblems.
He had received regular medical care and was meeting growth and developmental milestones on time.
The family history was negative. The father was of Mediterrean ethnicity and the mother is of Northern European ethnicity.
The pertinent physical exam at discharge showed a healthy male in no respiratory distress with mild rhinorrhea. His lungs were clear. His conjunctiva and mucous membranes were normally colored.
The patient’s clinical course included being placed on supplemental iron at 2-3 mg/kg/day of elemental iron. He was seen 5 weeks later.
His parents stated that he had been taking his iron and the physician noted grey staining of his teeth consistent with iron intake.
His CBC showed improved hemoglobin of 12.0 mg/dl but he had a continued low MCV of 62 fL. A ferritin level at that time was also decreased at 15.3% and he also had a normal lead level.
A hemoglobin electrophereis was ordered and showed an elevated Hemoglobin A2 at 3.6% (normal 1.5-3.4%). The parents were then screened and his mother had a hemoglobin A2 of 2.9% and his father’s was 3.5%. His father’s MCV was also decreased at 80 fL.
The diagnosis of beta-thalassemia minor and continued iron deficiency were made. He was placed on continued iron therapy for 3 months and his iron defiency was resolved. The family received genetic counseling.

Discussion
Anemia is a common problem in pediatrics. 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.
The most common type of anemia in childhood is iron deficiency comonly 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 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 of 10-20 g/L. If not other causes must be sought.

Learning Point
Dr. Thomas B. Cooley, the head of Children’s Hospital in Detroit first described thalssemias in 1925, and beta-thalassemia major is often referred to as Cooley’s anemia.
Beta-thalassemias are caused by abnormalities of the beta-gene on chromosome 11. The beta-globin chain may be produced in small amounts or not at all.
It commonly occurs in southern Italy, Greece and also in the the Middle East, Asia and the Indian subcontinent.
Beta-thalassemia minor or trait usually causes a mild decrease in the total amount of beta-globin chain and has a mild anemia without symptoms.
There is often microcytosis, hypochromia, target cells, elliptocytes and basophyllic stippling. The MCV is almost always below 75 fL, and the mean is 68 fL. The red cell distribution width is normal and Hemoglobin F levels are normal.
Iron deficiency anemia is often confused or occurs along with beta-thalassemia as both have microcytosis and hypochromia. The Mentzer index (MCV/RBC) is usually >12 in iron deficiency and <11 in thalassemia.
It is important to establish the diagnosis to avoid unnecessary treatment with iron and for genetic counseling. Prenatal screening is available to high risk populations or families.

Beta-thalassemia trait is commonly identified after an abnormal screening CBC does not show improvement despite adequate iron therapy.
Other causes of non-correcting anemias include:

  • Iron supplements not being taken
  • Severely depleted iron stores
  • Ongoing blood loss (e.g. hookworm, peptic ulcer disease, urinary or gastrointestinal tract loss, intravascular hemolysis, etc.)
  • Abnormal absorption (e.g histamine-2-blocks, gastric acid pump inhibitors, inflammatory bowel disease, etc.)

Questions for Further Discussion
1. How are the recommendations from the Centers for Disease Control different than from the American Academy of Pediatrics for anemia screening?
2. Is newborn screening for thalassemia done in the United States?
3. What other nutritional deficiencies present as anemia?

Related Cases

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

Information prescriptions for patients can be found at Pediatric Common Questions, Quick Answers for this topic: Anemia.

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

Rudolph CD, et.al. Rudolph’s Pediatrics. 21st edit. McGraw-Hill, New York, NY. 2003:1523-28, 1536-1539.

Green M. Palfrey JS, Clark EM, Anastasi JM, eds. 2000. Bright Futures Guidelines for Health Supervision of Infants, Children, and Adolescents. 2nd Edit. Pocket Guide. Arlington, VA: National Center for Education in Maternal and Child Health.

ACGME Competencies Highlighted by Case

  • Patient Care
    1. When interacting with patients and their families, the health care professional communicates effecively and demonstrates caring and respectful behaviors.
    2. Essential and accurate information about the patients is gathered.
    3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scientific evidence, and clinical judgment is made.
    4. Patient management plans are developed and carried out.
    5. Patients and their families are counseled and educated.
    9. Patient-focused case is provided by working with health care professionals, including those from other disciplines.

  • Medical Knowledge
    10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.
    11. Basic and clinically supportive sciences appropriate to their discipline are known and applied.

  • Practice Based Learning and Improvement
    13. Information about other populations of patients, especially the larger population from which this patient is drawn, is obtained and used.

  • Professionalism
    22. Sensitivity and responsiveness to patients’ culture, age, gender, and disabilities are demonstrated.

  • Systems Based Practice
    24. Cost-effective health care and resource allocation that does not compromise quality of care is practiced.
    25. Quality patient care and assisting patients in dealing with system complexities is advocated.

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

    Date
    December 19, 2005

  • On Physical Examination, What Differentiates Preseptal and Orbital Cellulitis?

    Patient Presentation
    A 3-year-old female came to her doctor for a decreased appetite and swelling around her right eye.
    She complained of pain in the right eye, cheek and head 1 day before.
    That morning her right eye was swollen shut, was red and continued to be painful.
    The past medical history showed a healthy child.
    The review of systems revealed that 2 weeks prior she had a fever and upper respiratory tract infection with some swelling around her left eye at that time. All symptoms resolved.
    The pertinent physical exam showed an somewhat ill-appearing pre-schooler with a temperature of 39.5 degree Celsius, heart rate 122, respirations 28 and a normal blood pressure.
    There was erythema, edema and warmth of the skin of the right eye over the entire globe that extends medially across to the left cheek, distally to the bottom of the nose and laterally to a line parallel to the lateral eye canthus.
    The sclera and palpebral conjunctiva were inflammed. There was full range of motion in the extraocular muscles bilaterally. Pupils were equal, round, reactive and 3-4 mm bilaterally. There is no photophobia. The rest of the examination was normal.
    The radiologic evaluation included an orbital computed tomography scan which showed right-sided preseptal cellulitis with no bony or retro-orbital involvement.
    The laboratory evaluation included a blood culture and a complete blood count that was normal except for a white blood cell count of 1.4 x 1000/mm2 with a 35% left shift.
    The patient’s clinical course included admission for intravenous cefuroxime.
    The patient continued to have significant pain, fevers in the 39-40 degree Celsius range and spread of the erythema radially in all directions over the next 36 hours.
    The patient was transferred to a regional children’s hospital where the repeat orbital computed tomography examination showed the diagnosis of orbital cellulitis both pre- and post-septally with a possible subperiosteal abscess.
    The abscess was successfully drained by Ophthalmology and a nasal-lacrimal duct stent was also placed to aid drainage.
    The antibiotics were changed to intravenous ampicillin/sulbactam and after 5 days were changed to oral amoxicillin/clavulanic acid for a total of 14 days of antibiotics.
    Cultures from the abscess and blood cultures were negative.


    Figure 30 – Axial image from a CT scan of the orbits performed without intravenous contrast. The image shows extensive pre-septal and post-septal inflammatory changes around the right orbit. Sinusitis of the ethmoid and maxillary sinuses is also seen. Because intravenous contrast was not given, a subperiosteal abscess cannot be excluded.

    Discussion
    Eye problems always raise concern with patients, families and health care providers because of the potential risk of vision loss. Thankfully, most problems are usually easily treated.

    The orbital septum is a fascial layer extending vertically from the orbital rim periosteum to the levator aponeurosis in the upper eyelid and to the inferior border of the tarsal plate in the lower eyelid.

    Preseptal cellulitis is anterior to the orbital septum is usually caused by Streptococcus species since the widespread immunization for Haemophilus influenzae type-B (HIB) which used to be the most common organism. Intravenous or oral antibiotics are usually given for 7-10 days.

    Orbital cellulitis is posterior to the orbital septum and is a ophthalmologic emergency. It is usually secondary to sinusitis often arising from the ethmoid sinuses. The common organisms are: Streptococcus species, Staphlococcus aureus and HIB.
    Generally children < 9 years have single organisms usually aerobic, but those > 9 years may have multiorganisms as the cause including anaerobes.
    Evaluation includes consultation with an ophthalmologist, computed tomographs of the orbital structures and sinuses. Gram-stain, smears and cultures of eye or nose drainage, infected sinus or abscess should be obtained if available.
    Broad spectrum antibiotics are usually given early in the clinical course for a duration of 2-3 weeks.
    Potential complications include subperiosteal or orbital abscess with possible compression of the optic nerve and blindness. Surgical drainage for abscesses is often indicated but intensive antibiotics may also suffice.

    Learning Point
    Preseptal cellulitis (also known as periorbital cellulitis) and orbital cellulitis are common infections of the eye structures. It can be difficult to clinically differentiate between preseptal and orbital cellulitis, although computed tomography may be of some assistance. If there is any doubt, then treatment for orbital cellulitis is begun.

    Preseptal cellulitis usually presents with usually well-demarcated edema and erythema of the periorbital skin and soft tissues.
    Children may be ill-appearing and can be quite sick but generally are less ill-appearing than children with orbital cellulitis

    With orbital cellulitis there characteristically is erythema and edema of the eyelids and periorbital tissues, painful eye movements, decreased vision, pupillary deficits and proptosis. The children are usually toxic appearing.


    Figure 31 – Clinical image of orbital cellulitis.

    In summary, both preseptal and orbital cellulitis may have:

    • Fever
    • Eyelid edema
    • Pain
    • Red eye
    • Child is ill-appearing

    Orbital cellulitis often has:

    • Decreased eye movement
    • Decreased vision
    • Papilledema
    • Proptosis

    The eyelid edema may be so significant that eyelid retractors are necessary to open the eyelids. Emergency eyelid retractors can be made from sterilized paperclips as shown below:

    12-05-05Figure32EyelidRetractors.jpg:
    Figure 32 – Picture of eyelid retractors.

    Questions for Further Discussion
    1. What are other ophthalmologic emergencies?

    Related Cases

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

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

    Fleisher GR, Ludwig S. Synopsis of Pediatric Emergency Medicine. Williams and Wilkins. Baltimore, MD. 1996:81-83, 735.

    Hardus, P, et.al. Appropriate Technology in Ophthalmology. Intermediate Technology Information Ring. 1996. Available from the Internet at http://www.who.int/ncd/vision2020_actionplan/documents/ITIR1996booklet.pdf (rev. 7/1/05, cited 10/13/05).

    Rudolph CD, et.al. Rudolph’s Pediatrics. 21st edit. McGraw-Hill, New York, NY. 2003:1218, 2409.

    Sobol AL. Preseptal Cellulitis. eMedicine.
    Available from the Internet at http://www.emedicine.com/oph/topic206.htm (rev. 7/1/05, cited 10/13/05).

    Centers for Disease Control. Public Health Image Library. Orbital Cellulitis. Image Number 2843. Available from the Internet at http://phil.cdc.gov (cited 10/13/05).

    ACGME Competencies Highlighted by Case

  • Patient Care
    1. When interacting with patients and their families, the health care professional communicates effecively and demonstrates caring and respectful behaviors.
    2. Essential and accurate information about the patients is gathered.
    3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scientific evidence, and clinical judgment is made.
    4. Patient management plans are developed and carried out.
    7. All medical and invasive procedures considered essential for the area of practice are competency performed.
    8. Health care services aimed at preventing health problems or maintaining health are provided.
    9. Patient-focused case is provided by working with health care professionals, including those from other disciplines.

  • Medical Knowledge
    10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.
    11. Basic and clinically supportive sciences appropriate to their discipline are known and applied.

  • Interpersonal and Communication Skills
    19. The health professional works effectively with others as a member or leader of a health care team or other professional group.

  • Systems Based Practice
    25. Quality patient care and assisting patients in dealing with system complexities is advocated.
    26. Partnering with health care managers and health care providers to assess, coordinate, and improve health care and how these activities can affect system performance are known.

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

    Date
    December 12, 2005

  • Did You Know That You Look a Little Yellow?

    Patient Presentation
    You have noticed that a 27-year-old male intern in your residency class seems to have a yellowish color to his skin and eyes in the mornings after being on-call.
    The yellow color seems to be worse when he had little sleep.
    The yellow color does not seem to be there on non-call mornings. After a couple weeks of noticing this, you finally are convinced that this pattern is real and decide to privately talk to him about it.
    He says that he has Gilbert’s Disease and it always is worse when he is stressed and overtired.
    He laughs, saying “I’ll probably be a pumpkin working in the ICU.”

    Discussion
    Jaundice describes the yellowish discoloration of skin, sclera and mucous membranes when there is an excess of bilirubin in the blood. It is clinically evident with bilirubin levels > 2 mg/dl in older children and 4-5 mg/dl in infants.
    The major source of bilirubin is the catabolism of hemoglobin.

    Gilbert’s Disease is caused by a common genetic phenotype and can be found in up to 10% of the general population ( up to 36% in Africans and up to 3% in Asians). It is caused by a change in the promoter for the bilirbuin uridine diphosphate glucuronyl transferase gene.
    The transcription of the gene is less active and therefore there is a relative deficiency of the enzyme. This causes a mild unconjugated hyperbilirubinemia (generally < 5 mg/dl) that is not associated with hepatocellular damage or hemolysis.
    The hyperbilirubinemia clinically presents at times of fasting or stress. Gilbert’s Disease has not been associated with any specific morbidity or mortality. It may explain cases of prolonged neonatal “physiologic” jaundice.

    Learning Point

    Causes of unconjugated hyperbilirubinemia include:

    • Cholestasis – intra- or extra-hepatic
    • Liver disease
    • Congenital hyperbilirubinemia – Crigler-Najjar Syndrome, Gilbert’s Disease
    • Hemolytic anemia
    • Fasting or malnutrition
    • Infection
    • Hyperthyroidism
    • Medications – i.e. oral contraceptives, estrogens
    • Menstruation
    • Reabsorption of extravastated blood

    Questions for Further Discussion
    1. What evaluation should be considered for unconjugated hyperbilirubinemia?
    2. What are the causes of conjugated hyperbilirubinemia?
    3. What causes physiologic jaundice in a neonate?

    Related Cases

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

    Information prescriptions for patients can be found at Pediatric Common Questions, Quick Answers for this topic: Jaundice.

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

    Bakerman S. Bakerman’s ABC’s of Interpretive Laboratory Data. Third Edit. 1994:89.

    Burchell B, Hume R. Molecular Genetic Basis of Gilbert’s Syndrome. J. Gastroenterology and Hepatology. 1999:14;960-9666.

    Rudolph CD, et.al. Rudolph’s Pediatrics. 21st edit. McGraw-Hill, New York, NY. 2003:1489.

    ACGME Competencies Highlighted by Case

  • Patient Care
    1. When interacting with patients and their families, the health care professional communicates effecively and demonstrates caring and respectful behaviors.

  • Medical Knowledge
    10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.

  • Practice Based Learning and Improvement
    13. Information about other populations of patients, especially the larger population from which this patient is drawn, is obtained and used.

  • Professionalism
    22. Sensitivity and responsiveness to patients’ culture, age, gender, and disabilities are demonstrated.

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

    Date
    December 5, 2005