PERPLEXING CONGENITAL HYPOTHYROIDISM INCIDENT IN A NEWBORN: A Case Study From Pediatric ESAP™
A nine-month-old female infant has congenital hypothyroidism that was initially detected through the state newborn program. On day one of life, her total T4 concentration (on blood spot analysis) was 5.0 μg/dL (<10th percentile), and her thyroid stimulating hormone (TSH) concentration was 738 mIU/L. On day eight of life, her serum-free T4 concentration was 0.61 ng/dL (normal range at eight days = 0.9-2.3 ng/dL), and her TSH concentration was 578 mIU/L. She was prescribed levothyroxine, 37.5 mcg daily (12 mcg/kg per day). Monitoring of thyroid function and levothyroxine dosing shows the following: Growth and development have been normal. After the dosage increase at seven months, her mother noted some fussiness and difficulty sleeping. QUESTION
The Pediatric Endocrine Self-Assessment Program (Pediatric ESAP™) is a self-study curriculum specifically designed for endocrinologists seeking initial certification or recertification in pediatric endocrinology, program directors interested in a training instrument, and clinicians seeking a self-assessment and a broad review of pediatric endocrinology. Pediatric ESAP is in both print and online formats with 100 multiplechoice questions in all areas of pediatric endocrinology, diabetes, growth, and metabolism. There is extensive discussion of each correct answer and references. Pediatric ESAP is updated biennially with new questions, and now available is the new Pediatric ESAP 2013–2014. Learn more at www.endoselfassessment.org.
A Pharmacy switching thyroid preparations
B Poor parental adherence to daily dosing regimen
C Mixing levothyroxine pill with soy protein formula
D Pituitary-thyroid hormone resistance from altered feedback axis
E Laboratory artifact due to heterophile TSH antibody
answer on page 26
Th is infant with congenital hypothyroidism manifests persistent serum TSH elevation despite serum free T4 levels above the upper reference range and increasing levothyroxine dosing. After the increase in the levothyroxine dosage at five months, testing at seven and nine months of age show a free T4 concentration above the reference range (note: the free T4 reference range for age can vary significantly with assay methods; it is important for clinicians to compare patient results with the reference range established for the specific assay used for their patient). In addition, the patient’s mother notes fussiness and difficulty sleeping, clinical features consistent with hyperthyroxinemia.
Th e best explanation for this set of laboratory data and clinical features is pituitary-thyroid hormone resistance from alteration of the negative feedback axis (Answer D). Th e hallmark of this condition is persistent elevation of serum TSH levels despite the prevailing serum free T4 concentration. Pituitary-thyroid hormone resistance is relatively common in infants with congenital hypothyroidism. One study reported a prevalence of 43% in infants younger than one year, decreasing to 10% in older children. These findings appear to result from an abnormal set-point for T4 control of TSH secretion associated with in utero hypothyroidism. It seems to improve with age, as noted by the prevalence numbers quoted above. Increasing the levothyroxine dosage in an attempt to suppress the serum TSH into the reference range often results in elevation of serum total T4 or free T4 above the reference range, with clinical features of hyperthyroxinemia, as was the case in this patient. Long-term overtreatment carries the risk of potential adverse effects.
Th ere are several brands of thyroid hormone and several forms of generic levothyroxine. Because the actual dose may vary slightly between the brand name and generic levothyroxine, studies show that switching preparations (Answer A) may result in a higher (or lower) serum TSH level. However, if this was the explanation of the TSH elevation in this case, one would expect the serum free T4 level to fall, not rise. Parental nonadherence to the treatment regimen (Answer B) also can affect serum thyroid function tests. If several doses have been missed and then quickly made up, for example, just before a blood test to check thyroid function, the serum free T4 may rise quickly into the normal range, but TSH may take a few weeks to fall into the normal range. However, most such infants will have experienced normalization of serum TSH levels, followed by a rise with missed doses. In addition, test results in this infant show a steady rise in the serum free T4 level as the dosage increases, evidence in favor of good regimen adherence. Thus, Answer B is unlikely to be correct. Soy protein binds levothyroxine and interferes with absorption. Mixing the pill with soy protein (Answer C) could lead to TSH elevation, but the serum free T4 level would be appropriately low. Heterophile antibodies, for example “human antimouse antibodies,” can produce erroneously high TSH results in some assays. Such antibodies present in early infancy would probably be of maternal origin, so their eff ect would be expected to disappear by four to six months of age. Thus, although the TSH elevation in this set of thyroid function test results could be explained by heterophile antibodies (Answer E), it is a less likely explanation than altered negative feedback.
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The answer is: D