Abstract
Background: For significant numbers of patients dissatisfied on standard levothyroxine (LT4) treatment for hypothyroidism, patient-specific responses to T4 could play a significant role.Aim: To assess response heterogeneity to LT4 treatment, identifying confounders and hidden clusters within a patient panel, we performed a secondary analysis using data from a prospective cross-sectional and retrospective longitudinal study.Methods: Multivariate and multivariable linear models adjusted for covariates (gender, age, and BMI) were stratified by disease-specific treatment indication. During follow-up, pooled observations were compared from the same patient presenting either with or without self-reported symptoms. Statistical analysis was extended to multilevel models to derive intra-class correlation coefficients and reliability measures during follow-up.Results: Equilibria between TSH, FT4, and FT3 serum concentrations in 342 patients were examined by treatment indication (benign goiter, autoimmune thyroiditis, thyroid carcinoma), consequently displaying complex interactive response patterns. Seventy-seven patients treated with LT4 and monitored for thyroid carcinoma presented, in association with changes in LT4 dose, either with hypothyroid symptoms or symptom-free. Significant biochemical differences appeared between the different presentations. Leveled trajectories by subject to relief from hypothyroid symptoms differed significantly, indicating distinct responses, and denying a single shared outcome. These were formally defined by a high coefficient of the intraclass correlation (ICC1, exceeding 0.60 in all thyroid parameters) during follow-up on multiple visits at the same LT4 dose, when lacking symptoms. The intra-personal clusters were clearly differentiated from random variability by random group resampling. Symptomatic change in these patients was strongly associated with serum FT3, but not with FT4 or TSH concentrations. In 25 patients transitioning from asymptomatic to symptomatically hyperthyroid, FT3 concentrations remained within the reference limits, whilst at the same time marked biochemical differences were apparent between the presentations.Conclusions: Considerable intra-individual clustering occurred in the biochemical and symptomatic responses to LT4 treatment, implying statistically multileveled response groups. Unmasking individual differences in the averaged treatment response hereby highlights clinically distinguishable subgroups within an indiscriminate patient panel. This, through well-designed larger clinical trials will better target the different therapeutic needs of individual patients.
Highlights
Despite lacking the minor component of triiodothyronine (T3) physiologically co-secreted with thyroxine (T4) by the healthy human thyroid gland, in thyroid failure monotherapy by levothyroxine (LT4) replacement remains the standard treatment for patients with primary hypothyroidism [1, 2]
Complex patterns emerge between TSH, FT4, and FT3 in patients treated with LT4 during follow-up in response to the treatment and changes in LT4 dose, displaying a high degree of intraclass correlation and multileveled structure
This invokes the danger of inappropriate statistical averaging in clinical trials, mandating a stronger focus on within-subject analyses according to ergodic principles
Summary
Despite lacking the minor component of triiodothyronine (T3) physiologically co-secreted with thyroxine (T4) by the healthy human thyroid gland, in thyroid failure monotherapy by levothyroxine (LT4) replacement remains the standard treatment for patients with primary hypothyroidism [1, 2]. Administered in variable doses, dose adequacy for a hypothyroid patient is determined by biochemically defined treatment targets based mainly on TSH measurements [2]. This marks a historical shift from earlier regimens primarily aiming at symptom relief [6]. Despite achieving appropriate biochemical treatment targets with LT4, as defined by current guidelines [2], a substantial fraction of patients continues to report persisting symptomatology expressing their dissatisfaction with the standard treatment [7]. While patients and doctors reported some success with the addition of T3 and guidelines by the European Thyroid Association acknowledge a potential benefit of T3/T4 combinations to some patients this subject overall remains contentious [7, 10,11,12]. For significant numbers of patients dissatisfied on standard levothyroxine (LT4) treatment for hypothyroidism, patient-specific responses to T4 could play a significant role
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