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Congenital Hypothyroidism – Monitoring Thyroid Function in Infants

Subjects had TFTs carried out monthly for the first six months of life and every one to two months between six and 12 months of age. Criteria indicating the need for monthly monitoring included:

• •

• change in dose within one month of a previous visit;

total T4 or fT4 levels not in upper half of normal range within one month of a previous visit;

TSH level of 5–10 µU/ml (less than twice the upper limit of normal) within one month of a previous visit associated with tT4/fT4 not in the upper half of normal range (to avoid inclusion of subjects with transient resistance to TSH sometimes reported in the first year of life in children with CH);

• TSH >10 µU/ml (more than twice the upper limit of normal) within one month of a previous visit, regardless of tT4/fT4 levels; and

• TSH <0.1 µU/ml.

When monitoring was conducted every other month, a TSH level of more than twice the upper limit of normal was regarded as an indicator of the need for more frequent monitoring – assuming that monthly monitoring would have picked up minor elevations in TSH, allowing earlier changes in L-T4 doses. Monthly monitoring appeared to be necessary in 74 % of children in the first six months of life and 36 % of children aged 6–12 months. These percentages would probably have been even higher if the goal of maintaining the TSH levels between 0.5 and 2.0 mU/l during the first three years of life had been used, as suggested by Baloch et al.13

Predictors of the need for monthly monitoring in the second six months of life included higher TSH and lower tT4 at diagnosis. Unfortunately, the overlap between the groups was such that monthly monitoring during the first year of life would seem to be necessary for all children diagnosed with CH, until further studies are available. These recommendations are closer to the previous AAP guidelines, published in 1993, which stated that TFTs should be monitored every one to two months during the first year of life, every two to three months between one and three years of age, and every three to 12 months until growth is complete.14

The frequency of monitoring of TFTs after three years of age has not been well studied, as fewer data are available regarding long-term outcomes of children with CH with suboptimal treatment after the age of three. The current AAP guidelines recommend monitoring TFTs every six to 12 months until growth is complete.

Assessing Permanency of Hypothyroidism Given the deleterious effect of under-treatment of CH during the first years of life, over-diagnosis is the inevitable price to pay for treating patients with transient hypothyroidism. To identify this subpopulation, children should be taken off thyroid replacement therapy for a trial period as soon as it is thought that a short period of untreated hypothyroidism will not have a significant effect on the developing brain.

The AAP recommends assessing the permanency of CH in children in whom an initial thyroid scan did not show an ectopic or absent gland, if the initial TSH was <50 mU/l and if there was no increase in TSH after the newborn period. Assessment of the permanency of CH should not be performed earlier than three years of age. Two options are suggested: either a trial off therapy for 30 days, or a reduction of the replacement dose by 50 % for 30 days, with subsequent TFTs to assess the effects. A permanent diagnosis of CH


is established if those TFTs are compatible with hypothyroidism. If they are normal after a 50 % dose reduction, medication should be discontinued for 30 days and new TFTs carried out at the end of the period. Any child given a diagnosis of transient hypothyroidism should be followed closely by the paediatrician, with TFTs carried out at any clinical suspicion of hypothyroidism. There are no established guidelines for the frequency of follow-up after withdrawal of thyroid hormone therapy.

Determining the aetiology of the child’s hypothyroidism may be helpful in deciding whether or not to temporarily withdraw replacement therapy.

Persistent Elevated Levels of Thyroid Stimulating Hormone

A combined regimen of L-T4 and T3 was thought to be a possible strategy for overcoming persistent TSH elevation, based on the postulate that non-suppressed TSH was secondary to lower T3 levels in the central nervous system, because approximately 20 % of T3 is secreted directly by the thyroid gland.

Levels of TSH remain elevated in some children with CH despite appropriate L-T4 treatment and normalisation of serum fT4 and tT4 levels. In this subpopulation, supraphysiologic T4 levels are required to suppress TSH levels. The precise mechanism is unclear but, in cases where adherence to treatment is not in question, it is thought that the setting of T4 negative feedback control on pituitary TSH secretion is abnormal. The treatment goal in this population is controversial. Maintaining normal T4 levels with an elevated TSH may be associated with an increased risk of thyroid nodules and cancer, but over-treatment may have a deleterious effect on growth and development and may affect school performance. In adults, combined L-T4 and triiodothyronine (T3) treatment protocols have lead to lower TSH levels.15

Combined L-T4 and T3 treatment was studied in a group of 10 children aged over five years with confirmed good adherence to treatment. All patients had a persistently high TSH level (>6.4 µIU/ml), which could only be normalised by supraphysiological L-T4 treatment, resulting in hyperthyroidism (fT4 above upper normal range). Patients were switched to a combined protocol, with half their L-T4 dose substituted with T3, in a 4:1 ratio. TFTs were monitored during a one-year follow-up period, and the doses of T3 and L-T4 were titrated to achieve normal TSH levels. All patients achieved normalisation of TSH without hyperthyroidism at a mean of seven months. Patients on the combined regimen had lower serum fT4 and tT4 levels and higher serum T3 levels compared with patients on L-T4 treatment alone.16

Genetic Causes of Congenital Hypothyroidism Eighty-five per cent of cases of CH are attributable to thyroid dysgenesis and 2 % of these are familial. Most of the genes implicated in thyroid dysgenesis are associated with phenotypic syndromes and would typically be diagnosed as a result of the associated anomalies. Examples are mutations in TTF-2, NKX2.1 and NKX2.5. Mutations in paired box gene eight (PAX8) were shown to cause thyroid dysgenesis, with no other congenital anomalies.4

Inborn errors of thyroid hormone biosynthesis account for 10–15 % of cases of congenital hypothyroidism. Mutations associated with dyshormonogenesis include sodium iodide symporter defects and thyroid peroxidase defects. Multiple causes of defects in thyroid peroxidase function have been described, including hydrogen peroxide


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