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Levothyroxine Treatment In Patients With Thyroid Cancer

Levothyroxine Treatment In Patients With Thyroid Cancer

The quest to establish effective therapy for hypothyroid obese patients remains ongoing, largely due to the challenge posed by thyrotropin-stimulating hormone (TSH) levels as a dependable marker of euthyroidism compared to nonobese patients. The positive correlation between TSH levels and body mass index (BMI) in obese individuals suggests a potential compensatory mechanism, possibly aimed at augmenting energy expenditure. However, the relationship between BMI and thyroid hormone levels remains enigmatic, as conflicting outcomes have emerged from diverse studies.

The determination of an appropriate L-T4 replacement dose proves more intricate for obese hypothyroid patients in contrast to their nonobese counterparts. Recent findings have hinted at a possible association between the L-T4 replacement dose and lean body mass in patients with obesity who have undergone thyroidectomy.

This study endeavors to unravel the intricate connections between the administered L-T4 dose, thyroid hormone levels, TSH secretion, basal metabolic rate (BMR), and total calculated deiodinase activity (GD) in athyreotic patients, both obese and nonobese. Furthermore, the research seeks to pinpoint tailored L-T4 replacement dose benchmarks, offering valuable insights for clinical implementation.

Introduction to Levothyroxine (L-T4) Treatment

Levothyroxine (L-T4) treatment is widely used to manage hypothyroidism, with established safety and pharmacological characteristics. The connection between obesity, thyroid disorders, and their clinical and molecular aspects has gained significance, given the growing global prevalence of obesity. However, treatment approaches for obese individuals with subclinical or overt hypothyroidism remain uncertain, involving factors like dosage form and combination therapy.

Successful L-T4 treatment hinges on restoring euthyroidism, often indicated by achieving age-adjusted thyrotropin-stimulating hormone (TSH) values. Interestingly, TSH levels in euthyroid subjects tend to rise with body mass index (BMI), potentially as a compensatory response to enhance energy expenditure. Conversely, the link between BMI and thyroid hormones (T4 and T3) remains unclear, with differing study outcomes. Recent findings suggest that the optimal L-T4 replacement dose in obese patients may be related to lean body mass, indicating the importance of individualized dosing.

To explore these intricacies, the study compares L-T4 dose, thyroid hormone levels, and TSH secretion with estimated basal metabolic rate (BMR) and total deiodinase activity (GD) in both obese and non-obese athyreotic subjects. The aim is to define personalized treatment targets for clinical testing, addressing the complexity of thyroid hormone interactions in energy homeostasis, metabolism, and body composition.


The study involved a retrospective assessment of 1150 patients who had undergone thyroid removal and received radioactive iodine (131I) treatment for differentiated thyroid cancer (DTC) at an outpatient clinic between 2010 and 2015. The patients’ thyroglobulin levels were within the range of 0.01 to 0.5 ng/ml, and they tested negative for antithyroglobulin antibody (TgAb). Since these patients lacked functional thyroid tissue, their circulating T4 levels were solely derived from levothyroxine replacement therapy. These individuals served as an excellent model to investigate the body’s ability to generate active hormones, with T3 originating from the conversion of administered T4.

Certain groups were excluded from the analysis, such as those with specific medical conditions (hypothalamic/pituitary, gastric, intestinal, neurological diseases), pregnant women, and individuals taking combined T3/T4 thyroid replacement therapy or other medications affecting thyroid hormone balance. Patients with variations in L-T4 dose, body weight, or thyroid hormone levels within three months prior to the study were also not considered. Ultimately, the analysis included 160 athyreotic patients under L-T4 therapy, all of whom exhibited euthyroid status based on their normal TSH, FT4, and FT3 levels.

Among them, circulating T4 levels originated solely from levothyroxine replacement therapy due to the absence of functional thyroid tissue. The analysis focused on patients with stable L-T4 doses, excluding those with certain medical conditions, medication interference, or recent dose changes, resulting in a final group of 160 athyreotic patients under L-T4 therapy.

The patient’s body mass index (BMI) was calculated based on weight and height, and obesity was defined as BMI ≥ 30 according to WHO criteria. Basal metabolic rate (BMR) was assessed using the Mifflin-St. Jeor formula, and deiodinase activity (GD) was calculated using the SPINA Thyr 4.2 algorithm. The study explored the relationship between L-T4 replacement dose, thyroid hormone homeostasis, BMR, and GD in both obese and non-obese patients. Additionally, the responsiveness of the hypothalamic/pituitary thyrotrope was evaluated using Jostel’s thyrotropin index. Statistical analyses were conducted to identify predictive variables associated with clinical outcomes.


The study analyzed 160 thyroidectomized patients who underwent 131I ablation for differentiated thyroid cancer. These patients were divided into two groups based on normal (≥21 nmol/s) or low (<21 nmol/s) deiodinase activity (GD). While sex, age, BMI, and BMR showed no significant differences between the groups, FT3 and the FT3/FT4 ratio were lower in patients with low GD. In contrast, low GD was associated with increased TSHI, FT4, LT-4 weekly cumulative dose, and the LT-4 × week/BMR ratio.

Binary logistic regression analysis revealed that LT-4 × week/BMR was inversely related to GD, while FT3 levels were directly related to GD. The study used a receiver operating characteristic (ROC) model to show that LT-4 × week/BMR > 0.56 mcg × week/kcal was a good predictor of reduced GD. Additionally, the study evaluated patients based on BMI, finding that FT3 and FT4 were higher in obese patients compared to non-obese patients. FT4 levels were positively related to BMI and negatively related to BMR, while pituitary thyreotropic activity (TSHI) was positively related to BMI and LT-4 × week/BMR, and inversely related to GD. The feedback sensitivity of thyroid hormones with the pituitary was notably different in obese and non-obese patients.

In summary, the study investigated the relationship between LT-4 dose, BMR, thyroid hormones, and GD in thyroidectomized patients. It also explored how these factors differed between obese and non-obese patients, shedding light on the complexities of thyroid hormone interactions.

  • Impaired T3 production and reduced T3/T4 ratio could lead to reduced FT3 levels and tissue exposure to circulating T3.
  • Previous research found a significant portion of levothyroxine-treated patients had reduced FT3/FT4 ratio.
  • Total deiodinase activity (GD) was assessed using the SPINA model, revealing higher LT-4 doses, increased FT4 and TSHI levels, and reduced FT3 levels in patients with impaired GD.
  • The study established an inverse relationship between GD activity and LT-4 × week/BMR, predicting GD impairment with a specific LT-4 × week/BMR value.
  • Similarities in BMR, BMI, age, and sex between patients with normal or reduced GD highlighted LT-4 dose and FT3 production as strong predictors of GD.
  • FT3 and FT4 were higher in obese patients, revealing differences in pituitary thyreotropic activity between non-obese and obese patients.
  • A defective hypothalamic-pituitary T4 to T3 conversion was observed in obese patients.
  • The study provided insights into the complex interactions among thyroid hormones, BMR, and obesity-related factors, potentially impacting treatment approaches.


The study highlights several significant insights. Firstly, around one-third of athyreotic patients on LT-4 replacement therapy exhibit reduced GD activity, which is linked to both LT-4 dosage and FT3 levels. Specifically, an LT-4 weekly cumulative dose of 0.56 mcg/kcal emerges as a notable predictor of diminished GD activity, while variables like sex, age, BMI, and BMR do not hold the same predictive weight. 

Secondly, in athyreotic patients with obesity, elevated FT4 levels suggest a potential resistance to LT-4 replacement therapy. These findings underscore the interplay between FT4 levels and BMI, with higher BMI negatively influencing BMR and subsequently impacting FT4 increment, especially in patients with greater lean body mass. 

Furthermore, the study hints at the involvement of various metabolic pathways in FT4 and FT3 degradation, suggesting a complex web of factors contributing to thyroid hormone regulation.

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