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INTRODUCTION
Differentiated thyroid cancer (DTC) includes papillary and follicular cancer, accounting for more than 90% of all thyroid cancers [1]. In DTC patients who have undergone total thyroidectomy (TT), it is important to suppress serum thyroid-stimulating hormone (TSH) by levothyroxine (LT4) replacement therapy in order to prevent tumor cell regrowth, which could be stimulated by TSH acting on the TSH receptors of thyroid cells [2,3].
Estimating the initial doses of LT4 for patients with hypothyroidism has typically relied on a formula that recommends 1.6 µg/kg of actual body weight (ABW) [4]. However, patients with DTC who have undergone thyroidectomy often require a higher LT4 dose to maintain normal TSH levels compared to those with primary hypothyroidism, and an even higher dose to suppress TSH [5]. When determining the appropriate LT4 dose, it is important to consider both the absence of thyroid function and the need for TSH suppression. Insufficient TSH suppression can increase the risk of tumor recurrence and lead to more frequent clinical visits. Conversely, overly aggressive TSH suppression can heighten the risk of adverse cardiovascular or skeletal effects, such as arrhythmias or osteoporosis, following surgery [6-8].
With the rising prevalence of obesity, body mass index (BMI) has been proposed as a factor to consider when determining the LT4 dosage. Numerous studies have shown a correlation between BMI and LT4 dosages in patients who have undergone thyroidectomy for benign thyroid conditions [9-12]. Given the findings of these studies, the LT4 dosage requirements may also differ according to BMI in DTC patients following thyroidectomy, but this relationship has not yet been established.
In this study, we investigated whether the LT4 dose, adjusted based on body weight, differs according to BMI in patients with DTC who have undergone TT. Additionally, we analyzed the relationship between the LT4 dose and BMI across different age subgroups of DTC patients after TT.
METHODS
Patient selection and clinical data
We reviewed the electronic medical records of 351 adult patients aged ≥18 years who underwent TT for DTC and visited the outpatient clinic of endocrinology at Samsung Medical Center between November 1, 2019 and March 31, 2020. A total of 228 patients were excluded for the following reasons: (1) TSH level below 0.1 mIU/L (n=3); (2) TSH level above 0.5 mIU/L (n=174); and (3) no BMI results (n=51). Finally, a total of 123 patients with mild TSH suppression (0.1 to 0.5 mIU/L) were included in the study (Fig. 1). Clinical data including age, sex, height (cm), body weight (kg), and current LT4 dose were obtained from the review. Patients were classified into four age groups: 20 to 39 years (n=17), 40 to 49 years (n=26), 50 to 59 years (n=39), and 60 to 89 years (n=41).
BMI was calculated by dividing ABW by height squared (kg/m2). According to the guidelines of the Korean Society for the Study of Obesity [13], BMI groups were divided into three categories: normal or underweight (BMI <23 kg/m2), overweight (23≤ BMI <25 kg/m2), and obese (BMI ≥25 kg/m2).
Serum TSH, triiodothyronine (T3), and free thyroxine (FT4) levels were measured using commercial kits (TSH—Immunotech, Marseille, France; T3 and FT4—RIA KIT, Immunotech). Each patient was assessed for the achievement of mild TSH suppression, which was defined as a TSH level of 0.1 to 0.5 mIU/L while maintaining a consistent LT4 dose over 6 months. Compliance with drug intake, including adequate ingestion method, was confirmed by the treating physician. This study was approved by the Institutional Review Board (IRB) of Samsung Medical Center and performed according to the Declaration of Helsinki (IRB number: 2020-04-091). Written informed consent by the patients was waived due to a retrospective nature of our study.
Statistical analysis
Continuous variables are expressed as the mean±standard deviation or median (interquartile range), and categorical variables are expressed as a number (percentage). The Student t test and Mann-Whitney U test were used to assess differences in continuous variables, and the Pearson chi-square test was used to assess differences in categorical variables between groups. Pearson correlation analysis was performed, and the Pearson Fcorrelation coefficient (r) was used to investigate the relationship between BMI and the LT4 dose. Linear regression analysis was performed to investigate associations between the LT4 dose and clinical factors. The collinearity of independent variables was assessed using the variance inflation factor (VIF) test, with a VIF ≥5 indicating collinearity. However, no collinearity was detected in the analyses that included the aforementioned variables. The Jonckheere-Terpstra test was performed to determine the presence of a statistically significant trend in LT4 dose related to ordinal groups categorized by BMI or age. The Kruskal-Wallis test and Mann–Whitney U test were used to identify the significant differences in the LT4 dose among the groups. Statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA). Two-sided P values <0.05 were considered statistically significant.
RESULTS
The clinical characteristics of the patients are presented in Table 1. Of the total patients, 94 (76.4%) were women and 29 (23.6%) were men. The mean age was 53.4 years and the median BMI was 23.9 kg/m2. The mean LT4 dose in relation to ABW was 1.80 µg/kg/day. Based on the demographic data, the BMI variable was divided into three categories: <23 kg/m2 (n=46), ≥23 and <25 kg/m2 (n=30), and ≥25 kg/m2 (n=47). No significant differences in serum TSH, T3, and FT4 levels were found among the BMI groups. The highest BMI group, consisting of obese patients, had a higher proportion of men and higher values for height, body weight, BMI, and absolute LT4 dose (µg) than the other BMI groups. The lowest BMI group had a higher LT4 dose based on body weight than the other groups. Patients in the overweight group were older than those in other groups.
Scatter plots of Pearson correlation coefficient between BMI and LT4 doses were generated (Fig. 2). BMI had a positive correlation with the absolute LT4 dose (r=0.5039, P<0.001) and an inverse correlation with the LT4 dose per kilogram of body weight (r=0.2742, P=0.002). In the univariable linear regression analyses for factors associated with LT4 dose, both BMI and age were inversely associated with the weight-based LT4 dose (Table 2). The multivariable linear regression model showed that both BMI and age continued to be inversely associated with the weight-based LT4 dose after adjusting for sex and height.
The difference in LT4 doses among ordinal BMI groups was analyzed via the trend test, and the results are shown in Table 3. There was a statistically significant trend for a lower weight-based LT4 dose in the higher BMI group (P for trend <0.001). Female patients also showed a significant inverse relationship between the weight-based dose of LT4 and BMI (P for trend <0.001). Female patients with a BMI <23 kg/m2 had significantly higher weight-based doses than overweight or obese female patients. The relationship between the weight-based dose of LT4 and ordinal age groups by age is shown in Table 4. An inverse trend was observed between the weight-based dose of LT4 and age groups (P for trend <0.001), which was consistent in female patients (P for trend <0.001). Among female patients, young adults aged 20 to 39 years had significantly higher weight-based LT4 doses than patients aged 50–59 or 60–89 years. In male patients, the weight-based LT4 dose had no significant relationship with age or BMI.
Further analyses were performed to determine which age groups had a significant difference in LT4 dose according to BMI (Table 5). In young adult patients aged 20 to 39 years, a lower BMI was significantly associated with a higher weight-based dose (P for trend=0.011). Since the number of male patients aged 20 to 39 (n=3) was too small to perform a trend test, female patients aged 20 to 39 years were further analyzed, revealing a significant trend between BMI and the weight-based dose (P for trend=0.016). Furthermore, there was a significant difference in the weight-based dose between the group with a BMI <23 kg/m2 and the obese group among all patients (2.30 µg/kg vs. 1.71 µg/kg) and female patients (2.30 µg/kg vs. 1.66 µg/kg) aged 20 to 39 years. In other age subgroups of patients, no significant trends were observed between BMI and the weight-based LT4 dose.
DISCUSSION
To the best of our knowledge, this is the first study to evaluate the required dose of LT4 for mild TSH suppression therapy (serum TSH between 0.1 and 0.5 mIU/L) in thyroid cancer patients after TT and to show a positive correlation between the weight-based LT4 dose and BMI. Benchmarking the required LT4 dose for achieving a target TSH range of 0.1 to 0.5 mIU/L post-DTC surgery makes it possible to extrapolate the initial LT4 dose needed for various other TSH ranges. Previous studies have reported a relationship between BMI and the required LT4 dose in patients who underwent TT, but research has focused primarily on benign thyroid diseases, such as Hashimoto’s hypothyroidism or Graves’ disease, treated with thyroidectomy.
Several body indices that could assist in determining the appropriate dosing of LT4 have been examined. The most widely used LT4 dosing formula, which is based on body weight, recommends 1.6 µg/kg for patients with primary hypothyroidism [4,14]. However, previous research has suggested that the LT4 dosing formula could be improved by including additional variables, such as BMI, to more accurately estimate the required LT4 dose [11,15]. The relationship between body surface area (BSA) and LT4 requirements has also been investigated. Al-Dhahri et al. [16] proposed a BSA-based model for LT4 dose adjustment, recommending 1.4 µg/kg/day for a BSA greater than 1.79 m2 and 1.7 µg/kg/day for a BSA of 1.79 m2 or less. Furthermore, studies by Mistry et al. [10] and Jin et al. [17] evaluated various body indices and concluded that ABW provided a more accurate estimation for LT4 dose titration than BSA, particularly after thyroidectomy in patients with non-malignant thyroid conditions. ABW and BMI are more practical for inclusion in the LT4 dosing formula in clinical settings, as they are easier to adapt compared to other indices like lean body weight or BSA, which require additional calculations.
Although the relationship between age and LT4 dosing remains a subject of debate [18,19], this study has confirmed a trend of decreasing weight-based LT4 dose requirements with advancing age. Additionally, for patients over 40 years of age, BMI was not a determining factor for the weight-based LT4 dose. In contrast, BMI demonstrated a significant correlation with LT4 dose according to the ABW in patients aged 20 to 39 years. The ongoing debate about whether age is a predictor for LT4 dosing may be partially explained by the reduced degradation of thyroxine that accompanies aging, which is likely due to the age-related decline in lean body mass [20]. Since muscle mass is associated with resting metabolism, the loss of muscle mass, known as sarcopenia, leads to a decrease in the basal metabolic rate (BMR) [21]. The aging process involves a reduction in both muscle mass and metabolic activity, resulting in a corresponding decrease in BMR [22]. Given the general decline in BMR with age, regardless of obesity [23], it appears that the LT4 dose may be more influenced by the age-related decrease in muscle mass and the subsequent reduction in BMR, rather than by the presence of obesity in the elderly population.
This study had several limitations. First, due to its retrospective nature, we could not eliminate the possibility of selection bias, and we did not account for other comorbidities or previous cancer treatments in our analysis, although all patients showed no evidence of residual cancer or recurrence. Second, the study population was exclusively Korean and predominantly female, which means that the definitions of obesity and the required LT4 doses may not be applicable to patients of other races and nationalities. Thirdly, we did not investigate the relationship between FT4 levels and LT4 doses in relation to body weight or BMI, as there was variability in the timing of LT4 intake among patients. This could lead to significant fluctuations in FT4 levels depending on when the LT4 was taken. Lastly, we did not consider other body weight indices such as ideal body weight and lean body weight in this study. Despite these limitations, the study suggests that BMI, which is easily measured in a clinical setting, could be a useful predictor of LT4 dose requirements alongside body weight. This highlights the importance of further research into an LT4-dosing formula that incorporates BMI.
In conclusion, we proposed a benchmark LT4 dose for mild TSH suppression after surgery in patients with DTC. Furthermore, lower BMI was associated with a higher body weight-based LT4 dose required to achieve mild TSH suppression, particularly in young adults 20 to 39 years. Therefore, clinicians might consider a higher body weight-based LT4 dose in young adults with lower BMI than in patients with a higher BMI or age over 50 years.
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