ESPE Abstracts

Background: Pituitary resistance to exogenous thyroxine (RETH) refers to persistently elevated serum TSH levels despite high/normal T4 concentrations in levothyroxine-treated patients. The underlying mechanisms and natural history of RETH in children with congenital hypothyroidism (CH) are not well known.

Objective: We aimed to describe the possible mechanisms and natural history of RETH in children with CH.

Patients and Methods: We retrospectively reviewed the medical records of 508 patients with permanent primary CH. The criteria for RETH were persistently elevated TSH levels despite target fT4 levels (the upper half of the reference interval) and returning to normal only by clinical or biochemical hyperthyroidism Genetic testing was performed using an accustomed 23-gene panel in RETH patients (n: 14) with gland in situ (GIS) and hypoplastic thyroid. After the exclusion of patients with TSHR gene variants (n:11), the overall course of TSH levels and fT3/fT4 ratios in the remaining RETH patients (n: 37) were analyzed and compared with age-, gender-, and thyroid morphology-matched non-RETH patients (n: 37).

Results: A total of 48 patients (9.4%) met RETH criteria, and 11 of them (23%) had TSHR gene variants. While 83% (n:40) of RETH patients had thyroid dysgenesis, this rate was 58% in non-RETH patients (P = 0.001). RETH was present from birth in 38% of patients, whereas in others, it developed later at a median age of 1.9 (1.1-9.0) years. RETH did not resolve in any patient during an average follow-up period of 9.8±3.4 (4.3-17.5) years. Although there was no difference at baseline, RETH patients had higher TSH levels than non-RETH patients from the first year onwards (P = 0.001), especially when fT4 levels were below or within target limits. In RETH patients, serum TSH increased sharply from age 2 years, and reached peak levels between ages 5 and 7 years (median 69, 25 and 6,5 mU/l, with fT4 levels below, within and above target, respectively). After age 10, it declined to moderately elevated levels but never returned to normal. Also, fT3/fT4 in RETH patients were lower than in non-RETH patients, especially between ages 2 and 10 years (P <0.05)

Conclusion: RETH in children with CH is not a uniform clinical condition. In RETH patients with GIS and hypoplastic thyroid, TSH receptor resistance may be the main underlying mechanism for upwardly adjusted TSH setpoint. In patients with thyroid ectopia or athyreosis, RETH may be due to decreased type 2 deiodinase activity, as reflected by low fT3/fT4 ratios.