Improving hormonal balance in the treatment of pediatric congenital hypothyroidism: the role of combined LT4-LT3 therapy

Giacco Luisa Del; Marco Abbate; Gaia Vincenzi; Petralia Ilenia Teresa; Giulia Tarantola; Cristina Santagiuliana; Sara Zanelli; Vigone Maria Cristina

doi:10.1530/endoabs.110.P1129

JOINT3871

Introduction: Congenital hypothyroidism (CH) is managed with levothyroxine (LT4) to normalize TSH levels. However, LT4 monotherapy does not always ensure adequate tissue euthyroidism due to variability in peripheral conversion of thyroxine (T4) to triiodothyronine (T3). The FT3/FT4 ratio has emerged as a sensitive marker of thyroid hormone balance, with a persistently low ratio suggesting suboptimal T3 availability, as T3 is the biologically active hormone primarily generated from peripheral T4 conversion. This study investigates whether the addition of liothyronine (LT3) to standard LT4 therapy can restore a physiological FT3/FT4 ratio in pediatric CH patients.

Methods: 15 pediatric CH patients with an altered FT3/FT4 ratio, despite normal or high-normal TSH and FT4 levels, were enrolled. Notably, 53% of patients had TSH and FT4 within range but with FT4 value at the upper limit and TSH at the high-normal threshold, making LT4 dose adjustments challenging. LT3 was introduced gradually, targeting an LT4:LT3 dose ratio between 10:1 and 20:1 to approximate physiological hormone production. Thyroid function tests (TSH, FT4, FT3, FT3/FT4 ratio) were evaluated according to age-specific reference ranges and measured at baseline, within six months of LT3 initiation, upon FT3/FT4 ratio normalization, and at a subsequent stability evaluation.

Results: At baseline, all patients exhibited an altered FT3/FT4 ratio, suggesting inadequate conversion of T4 to T3. Following LT3 introduction, FT4 levels decreased significantly (p=0.0005), while FT3 increased modestly, leading to progressive normalization of the FT3/FT4 ratio. The 92% of patients who achieved a normalized FT3/FT4 ratio, remained stable at the final follow-up (p<0.0096). Correlation analysis suggested that even small LT3 doses contributed significantly to optimizing thyroid balance.

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Parameters	Pre-therapy w/lT3	1° evaluation	2° evaluation	3° evaluation	p-value
TSH (mcU/mL)	5.49(1.27-7.58)	2.53(0.70-8.13)	2.64(0.78-5.48)	2.16(2.16-3.6)	0.349
FT4 (pmo/l)	25.67(±6.32)	21.40(±3.00)	19.31(±2.7)	19.11(±2.33)	0.0005
FT3 (pmol/l)	6.69(±0.63)	9.96(±0.70)	6.92(±0.70)	7.04(±0.72)	0.230
FT3/FT4	0.29(±0.04)	0.36(±0.03)	0.38(±0.02)	0.39(±0.05)	0.0037

Conclusion: Our results suggest that the addition of LT3 to standard LT4 therapy can help restore a physiological FT3/FT4 ratio in pediatric CH patients with altered peripheral conversion. This approach may provide a more physiologic thyroid hormone balance, where LT4 monotherapy fails to optimize tissue hormone availability. While these results highlight the potential benefits of combination therapy, careful titration dose and monitoring therapy remain crucial. Future studies with larger cohorts and long-term follow-up are needed to refine treatment strategies and personalize the management of CH.

Endocrine Abstracts

P1129