Correspondence

Case 3-2009: A 9-Month-Old Boy with Seizures

N Engl J Med 2009; 360:1572-1574April 9, 2009

Article

To the Editor:

In the Case Record of a patient with hypocalcemic seizures due to vitamin D deficiency, discussed by Holick et al. (Jan. 22 issue),1 it is surprising to note that in spite of these seizures, he was treated with fosphenytoin twice. Phenytoin accelerates metabolism of 1,25-dihydroxyvitamin D because of induction of the cytochrome P-450 system, and it will lead to exacerbation of hypocalcemia and seizures.2-4 Phenytoin also is implicated in end-organ resistance to the biologic effects of 1,25-dihydroxyvitamin D.4

Ajit Singh Kashyap, M.D.
Command Hospital, Lucknow 226 002, India
kashyapajits@gmail.com

Kudip Parkash Anand, M.D.
Pravara Institute of Medical Sciences, Ahmednagar 412304, India

Surekha Kashyap, M.D.
Command Hospital, Lucknow 226 002, India

4 References

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   Case Records of the Massachusetts General Hospital (Case 3-2009). N Engl J Med 2009;360:398-407
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   Khosla S. Hypercalcemia and hypocalcemia. In: Fauci AS, Braunwald E, Kasper DL, et al., eds. Harrison's principles of internal medicine. 17th ed. Vol. 1. New York: McGraw-Hill, 2008:285-7.
   

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   Pack AM, Gidal B, Vazquez B. Bone disease associated with antiepileptic drugs. Cleveland Clin J Med 2004;71:Suppl 2:42-48
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   Bringhurst FR, Demay MB, Krane SM, Kronenberg HM. Bone and mineral metabolism in health and disease. In: Fauci AS, Braunwald E, Kasper DL, et al., eds. Harrison's principles of internal medicine. 17th ed. Vol. 2. New York: McGraw-Hill, 2008:2365-77.
   

To the Editor:

Holick et al. diagnosed iron deficiency with α-thalassemia trait, but this may not be the whole story. Anisocytosis is sensitive, but not specific for iron deficiency.1 Hypochromia was noted in the peripheral-blood smear, but a normal mean corpuscular hemoglobin concentration, indicative of “normochromic” red cells, argues against iron deficiency. The authors state that the low transferrin saturation of 4.9% confirms the diagnosis of iron deficiency. However, transferrin saturation depends on iron consumption in the previous 24 to 48 hours, during which time this patient was intubated. Transferrin saturation has a poor positive predictive value for iron deficiency, even in healthy children.2

A red-cell count of more than 5 (calculated as the hematocrit divided by the mean corpuscular volume) and a Mentzer's index of less than 13 (calculated as the red-cell count divided by the mean corpuscular volume) argue for thalassemia trait rather than iron deficiency.3 Iron deficiency and α-thalassemia trait both commonly yield low levels of hemoglobin A₂, whereas this patient had an elevated level of hemoglobin A₂, which is classically seen in β-thalassemia.4 Considering the microcytosis, low Mentzer's index, high volume of red cells, normal mean corpuscular hemoglobin concentration, elevated level of hemoglobin A₂, and low level of hemoglobin S, an intriguing explanation might be a “thalassemic” sickle cell gene locus or an α-gene triplicate syndrome.5 Of course, if the mean corpuscular volume normalized after iron therapy, this would suggest iron deficiency.

Paul Kent, M.D.
Becky Smeraglinolo, M.D.
Doan Le, B.A.
Rush University Medical Center, Chicago, IL 60612

5 References

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   Rempher KJ, Little J. Assessment of red blood cell and coagulation laboratory data. AACN Clin Issues 2004;15:622-637
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   Milman N, Cohn J. Serum iron, serum transferrin and transferrin saturation in healthy children without iron deficiency. Eur J Pediatr 1984;143:96-98
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   Hermiston ML, Mentzer WC. A practical approach to the evaluation of the anemic child. Pediatr Clin North Am 2002;49:877-891
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   Alperin JB, Dow PA, Petteway MB. Hemoglobin A2 levels in health and various hematologic disorders. Am J Clin Pathol 1977;67:219-226
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   The thalassemias. In: Nathan DG, Orkin SH, Ginsburg D, Look AT. Nathan and Oski's hematology of infancy and childhood. 6th ed. Vol. 1. Philadelphia: W.B. Saunders, 2003:842-919.
   

Author/Editor Response

With regard to the comments by Kashyap et al.: although it is true that vitamin D deficiency and hypocalcemia can develop in children who are receiving several antiseizure medications for a long time, there are no data to suggest that giving an antiseizure medication such as phenytoin as short-term treatment to control seizures will cause vitamin D deficiency and hypocalcemia precipitously. It is now recognized that many antiseizure medications, glucocorticoid agents, AIDS drugs, and even St. John's wort activate the steroid xenobiotic receptor, which in turns binds the retinoic acid X receptor. This complex binds to the vitamin D–responsive element for the 25-hydroxyvitamin D-24-hydroxylase, which accelerates the catabolism of both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D.1 There is no contraindication for the use of antiseizure medications during acute seizure activity, since they do not cause vitamin D deficiency or worsen hypocalcemia in patients with acute disease. We do agree that because phenytoin increases target-organ resistance to 1,25-dihydroxyvitamin D, it is not the best choice for treatment. Indeed, when it became clear that the seizure activity was due to hypocalcemia, anticonvulsant agents were discontinued. During this same time period, supplemental calcium and 1,25-dihydroxyvitamin D were administered to this boy, reducing the possibility of phenytoin-induced hypocalcemia.

In response to the comments by Kent et al.: we agree that the attempted diagnosis of iron deficiency in a recently intubated, acutely ill child is fraught with many potential pitfalls, including the acute-phase response and iron consumptive processes. As they pointed out, the red-cell indexes are suggestive of a concomitant thalassemia. Kent et al. suggested that the elevated level of hemoglobin A₂ provided evidence of β-thalassemia, but this correlation is not so clear-cut. In the system of high-pressure liquid chromatography that was used in this case, the presence of hemoglobin S resulted in artifactual elevation of hemoglobin A₂.2 Thus, the elevated level of hemoglobin A₂ did not rule out the diagnosis of α-thalassemia or provide strong evidence of a diagnosis of β-thalassemia.

In follow-up complete blood counts, the anemia resolved rapidly when the patient received supplementation with iron and multivitamins. In addition, in subsequent complete blood counts, the patient's mean corpuscular volume has remained low and the red-cell count has remained high, suggesting a mild thalassemic trait. Follow-up analysis of the hemoglobin level and possible genetic analysis of the globin loci have been recommended to provide a definitive diagnosis. The intriguing possibilities mentioned by Kent et al. are certainly in play, as is the more prosaic α-thalassemia trait.

Michael F. Holick, M.D., Ph.D.
Boston University Medical Center, Boston, MA 02118
mfholick@bu.edu

Nicole A. Sherry, M.D.
Anand S. Dighe, M.D., Ph.D.
Massachusetts General Hospital, Boston, MA 02114

2 References

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   Zhou C, Assem M, Tay JC, et al. Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia. J Clin Invest 2006;116:1703-1712
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   Suh DD, Krauss JS, Bures K. Influence of hemoglobin S adducts on hemoglobin A2 quantification by HPLC. Clin Chem 1996;42:1113-1114
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