Explanations for disparate fT4 and TSH results in infants and children with primary congenital hypothyroidism

Possible explanation	Clinical clues/investigation	Next steps
Pattern 1: fT4 in the upper one-half of the reference range, and TSH mildly elevated (eg, 5 to 20 mU/L)
Child was given extra doses of levothyroxine just before scheduled blood test monitoring, to make up for missed doses	Parents/caregivers confirm that they gave extra doses before testing	Do not increase levothyroxine dose Encourage close adherence to regimen Recheck thyroid function tests in 1 month
Mild underdosing*	Parents/caregivers report that they did not give extra doses before testing	Make a small increase in levothyroxine dose Recheck serum fT4 and TSH in 1 month Children who were mildly underdosed will be euthyroid after this dose adjustment
Thyroid hormone resistance^¶	Previous dose increases did not normalize TSH and/or child has signs of thyrotoxicosis^Δ	Do not increase levothyroxine dose; if the levothyroxine dose is increased to normalize TSH, patients may develop thyrotoxic clinical features If the child has thyrotoxic clinical features, reduce the levothyroxine dose
Pattern 2: fT4 elevated, and TSH in the normal reference range
The elevated fT4, though higher than this patient's "physiologic set point," is required to generate normal T3 levels^◊	Review diagnostic evaluation for congenital hypothyroidism, including thyroid ultrasound results	Do not decrease levothyroxine dose^§
The fT4 reference range reported for this assay is not appropriate for neonates or infants, who tend to have higher normal reference ranges	Review reference range for the neonate's or infant's age (refer to UpToDate content on diagnosis of congenital hypothyroidism)	Do not decrease levothyroxine dose^§
The fT4 is normal for this patient because their "physiologic set point" is slightly above the upper end of the listed reference range	This explanation is likely if fT4 elevation is mild and persistent and if the above causes are excluded	Do not decrease levothyroxine dose^§

fT4: free thyroxine; TSH: thyroid-stimulating hormone; T3: triiodothyronine.

* Mild underdosing occasionally causes this "disparate" pattern of mildly elevated TSH with normal fT4. More commonly, underdosing causes elevated TSH with low or low-normal fT4.

¶ Many infants have transient mild thyroid hormone resistance during infancy (due to resetting of the pituitary-thyroid feedback threshold because of intrauterine hypothyroidism). The pattern is more common in infants than in older children (43 versus 10%, respectively, in 1 study)^[1].

Δ Symptoms and signs of thyrotoxicosis in an infant include tachycardia, stare, irritability, hyperactivity, restlessness, and poor sleep.

◊ One example of an altered set point is an individual with thyroid aplasia who produces 20% less T3 compared with those with a normal thyroid gland.

§ In these scenarios, the elevated fT4 does not indicate overtreatment, because TSH is normal.

Reference:

Fisher DA, Schoen EJ, LaFranchi S, et al. The hypothalamic-pituitary-thyroid negative feedback control axis in children with treated congenital hypothyroidism. J Clin Endocrinol Metab 2000; 85:2722.

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Explanations for disparate fT4 and TSH results in infants and children with primary congenital hypothyroidism