Relationship between TSH and Free Thyroxine in Outpatient Cancer Patient Population
Authors: Alkhalaileh Hussam , Wei Ruhan , Lee Jason K.Y. , Jones JoAnna , Li Jieli 
Published: January 2023

Abstract
Background
The inverse log-linear relationship between Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) is well established and reliably used for evaluation of hypothalamus-pituitary-thyroid (HPT) axis function. However, there are limited data regarding oncologic states in the TSH-FT4 relationship. The purpose of this study was to evaluate thyroid pituitary hypothalamic feedback regulation by the inverse log TSH and FT4 relationship in the cancer patient population at the Ohio State University Comprehensive Cancer Center (OSUCCC-James).
Methods
This retrospective study analyzed the correlation between TSH and FT4 results from 18846 outpatient subjects collected in August 2019-November 2021 at the Department of Family Medicine (OSU Wexner Medical Center), Department of Oncology (OSUCCC-James). Patients with diagnoses related to cancers were included in the oncology group. Patients with diagnoses not related to cancers were included in the non-oncology group. Patients of the Department of Endocrinology, Department of Cardiology, Department of Obstetrics & Gynecology and Department of Hematology were excluded from this study. Time of collection for TSH and FT4 was from 7am to 7pm. Data were analyzed by morning (7am-12pm) and afternoon (12pm-7pm). Spearman correlation and non-linear fit were used for data analysis. Sex differences were analyzed as well in each group.
Results
Overall, an inverse correlation was observed between TSH and FT4 in both groups (non-oncology and oncology) regardless of sample collection time and sex differences. Further analysis by linear model in log TSH and FT4 showed a significant inverse fit in males compared with females in the oncology group of oncology, both in the afternoon (p < 0.05). Data were further analyzed by ranges of FT4, as lower or higher (pathophysiology) or within (physiology) the reference interval of FT4. There was no statistical significance between the non-oncology and oncology groups, but better correlation in non-oncology in either physiological or pathophysiological FT4 levels and sample collection time. Interestingly, the best correlation between TSH and FT4 was found in the non-oncology group at pathophysiological FT4 concentrations (abnormally high). In addition, at pathophysiological FT4 concentrations (abnormally low), the oncology group demonstrated a significant TSH response in the morning than in the afternoon (p < 0.05).
Conclusions
Though overall the TSH-FT4 curves showed an inverse relationship, there are variations of TSH-FT4 relationship for collection times when considering FT4 in physiological or pathophysiological states. The results advance understanding of TSH response, which is beneficial for the interpretation of thyroid disease. It is not recommended to evaluate thyroid pituitary hypothalamic axis by TSH results when FT4 is abnormally high in oncology patients or low in non-oncology patients, due to poor predictability and the potential for misdiagnosis. A better understanding of the complex nature of the TSH-FT4 relationship may need further study with better defining subclinical states of cancer patients.