Background: Primary congenital hypothyroidism (CH) is one of the most common endocrine disorders in children. To prevent irreversible brain damage, early diagnosis and prompt Levothyroxine (LT4) replacement are necessary. Many guidelines recommend high dose LT4 (10-15 µg/kg/day) for rapidly normalizing thyroid hormone levels. However, iatrogenic hyperthyroidism was occasionally reported by using this dosage range. LT4 treatment is discontinued at three years of age to determine whether they are transient or permanent CH. Identify factors for predicting permanent CH may avoid unnecessary LT4 cessation.
Objectives: We studied infants with primary CH to determine prevalence and factors for predicting iatrogenic hyperthyroidism in the first month of LT4 treatment. The prevalence and predictive factors of permanent CH were also analyzed.
Methods: This was a retrospective cohort study in 87 infants with primary CH treated at Chiang Mai University Hospital from 2007 to 2020. Primary CH was defined by positive neonatal TSH screening (nTSH) and elevated confirmatory TSH with low or normal free T4 levels. Infants born to mother with Graves’ disease were excluded. Patients were classified by thyroid status at four weeks after LT4 initiation as hypothyroidism, euthyroidism, and iatrogenic hyperthyroidism. Demographic data, thyroid functions, and LT4 dosage at treatment initiation and all follow-up visits were compared between groups. At the age of 3 years, patients were assigned as permanent or transient CH, depending on the requirement of LT4 after discontinuing the treatment. The differences between groups were analyzed.
Results: At four weeks after LT4 initiation, 35.6% were classified as iatrogenic hyperthyroidism, 47.1% as euthyroidism, and 17.2% as hypothyroidism. A cutoff initial LT4 dose of 10.2 µg/kg/day had a sensitivity of 64.5 % and a specificity of 71.4% for predicting iatrogenic hyperthyroidism which was identified in 55.6% and 21.6% of patients treated with an initial dose of ≥ 10.2 µg/kg/day and <10.2 µg/kg/day, respectively (p=0.004). Initial LT4 dose was the only predictive factor for thyroid status after initial treatment. During the first-year follow-up, the prevalence of hyperthyroidism was 29.4%, 26.8%, 16.1%, and 4.5% at 2, 4, 6, and 12 months of age, respectively. After discontinuing LT4 replacement at the age of three, 27 out of 57 (47.4%) were diagnosed with permanent CH, whereas 52.6% did not require LT4 replacement. Thirteen (48.1%) and eight (26.7%) patients with permanent and transient CH experienced hyperthyroidism at the first follow up visit, respectively. The dosage of LT4 at three years of age was significantly higher in patients with permanent CH (3.3 [2.6-4.2] vs. 2.85 [1.85-3.1] µg/kg/day, p=0.02). LT4 dosage at three years of age was the only predictive factor for permanent CH.
Conclusion: Iatrogenic hyperthyroidism is common in infants with primary CH treated with recommended LT4 dosage. Both permanent and transient CH patients experience iatrogenic hyperthyroidism. LT4 dose is the only factor for predicting thyroid status after LT4 treatment and the diagnosis of permanent CH.
Keyword Congenital hypothyroidism, Levothyroxine, Prevalence, Predictive factor, Dose
