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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0534
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 7 4047-4050
Copyright © 2005 by The Endocrine Society

Influence of Human Body Composition on Serum Peak Thyrotropin (TSH) after Recombinant Human TSH Administration in Patients with Differentiated Thyroid Carcinoma

Maria Grazia Castagna, Aldo Pinchera, Alessandro Marsili, Monica Giannetti, Eleonora Molinaro, Paola Fierabracci, Lucia Grasso, Furio Pacini, Ferruccio Santini and Rossella Elisei

Department of Endocrinology and Metabolism (M.G.C., A.P., A.M., M.G., E.M., P.F., L.G., F.S., R.E.), University of Pisa, 56100 Pisa, Italy; Department of Internal Medicine, Endocrinology and Metabolism, and Biochemistry (F.P.), University of Siena, 53100 Siena, Italy; and AmbiSEN Center, High Technology Center for the Study of the Environmental Damage of the Endocrine and Nervous Systems (A.P.), University of Pisa, 56124 Pisa, Italy

Address correspondence and requests for reprints to: R. Elisei, M.D., Department of Endocrinology, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy. E-mail: relisei{at}endoc.med.unipi.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Objectives: In this study, we evaluated the influence of height, weight, body mass index (BMI), body surface area, and body composition [total lean body mass (LBM) and fat body mass] on serum peak TSH levels obtained after recombinant human (rh)TSH. Furthermore, to verify whether the serum peak TSH influenced the efficacy of radioiodine (131I), we compared the rate of thyroid remnant ablation according to the patients’ BMI.

Patients: We studied 105 patients with differentiated thyroid carcinoma who underwent rhTSH stimulation test. Serum TSH measurements were performed before and 24, 48, and 72 h after rhTSH administration. We also compared the rate of thyroid remnant ablation among 70 differentiated thyroid carcinoma patients with different BMI.

Results: The serum peak TSH after rhTSH was significantly lower in overweight and obese subjects compared with normal-weight subjects (92.1 ± 41.8, 82.4 ± 24.2, and 112.7 ± 46.3 µU/ml, respectively; P = 0.01) and in males compared with females (74.6 ± 22.3 and 105.0 ± 43.0 µU/ml, respectively; P = 0.0002). By univariate analysis, serum peak TSH was negatively related to weight, height, body surface area, BMI, LBM, and fat body mass, but only LBM was independently associated with serum peak TSH levels. Although it was confirmed that overweight and obese patients had a lower serum peak TSH, the rate of ablation did not differ among normal-weight, overweight, and obese patients.

Conclusions: With this study we demonstrated that LBM is the only parameter independently associated with serum peak TSH after rhTSH administration. However, the serum peak TSH does not influence the rate of 131I remnant ablation.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
ONE OF THE most challenging problems in clinical pharmacokinetics is the development of optimal methods for individualizing drug dosage. Drug dosage is based on anthropometric features, such as total body weight or surface area, and on creatinine clearance. Among all these parameters, lean body mass (LBM) has been indicated as the one that better correlates with the dosage of hydrophilic drugs. This finding is in keeping with the observations that the volume of distribution of drugs correlates with LBM, that most metabolic processes occur within lean tissue, and that both kidney and liver, which are responsible for drug elimination, are part of this compartment (1, 2, 3).

In recent years, the use of recombinant human (rh)TSH has been introduced in the follow-up of patients affected by differentiated thyroid carcinoma (DTC). The im administration of rhTSH, while DTC patients are on L-T4 therapy, increases both radioiodine uptake and thyroglobulin (Tg) secretion if normal or metastatic thyroid tissue is present after total thyroidectomy (4, 5). The possibility of using the rhTSH stimulus also for 131I ablation of the postsurgical thyroid remnant has been widely debated (6, 7, 8), and finally, the results of a multicentric clinical trial demonstrated that the rate of ablation is similar when patients are treated after rhTSH administration or L-T4 withdrawal (9).

Recently, it has been reported that, among several parameters, including age, height, weight, body surface area (BSA), and body mass index (BMI), only BSA was independently associated with serum peak TSH levels after rhTSH administration, thus suggesting the opportunity to personalize the dosage of rhTSH for ameliorating the efficacy of the rhTSH stimulus (10).

Because rhTSH is a hydrophilic drug (11), we evaluated the influence of body composition [LBM and fat body mass (FBM)] on serum peak TSH levels obtained after rhTSH administration in patients with DTC treated with total thyroidectomy and radioiodine ablation. With the attempt to clarify whether the dosage of rhTSH should be personalized, the influence of serum peak TSH levels on the rate of ablation of the postsurgical thyroid remnant was also evaluated.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
We investigated 105 patients (73 females and 32 males; female to male ratio, 2.2:1) with DTC already treated with total thyroidectomy and 131I remnant ablation, selected on the basis of BMI. They were equally distributed into three groups: 35 normal-weight (BMI = 18.5–24.9 kg/m2), 35 overweight (BMI = 25–29.9 kg/m2), and 35 obese (BMI ≥ 30 kg/m2) subjects. Patients were treated with a suppressive dose of L-T4 (mean value of basal TSH, 0.10 ± 0.13 µU/ml; range, 0.005–0.8 µU/ml; median, 0.06 µU/ml). Each patient received a standard dose of 0.9 mg rhTSH im for two consecutive days according to the conventional protocol (5). Blood samples were taken for the dosage of TSH before the first administration of rhTSH as well as 24, 48, and 72 h after the second administration of rhTSH. Total LBM and FBM were measured by dual-energy x-ray absorptiometry scan and analyzed with the manufacturer’s whole-body version (Hologic QDR 4500A; Hologic, Inc., Waltham, MA). All patients attended for routine follow-up and gave informed consent to the investigation.

Seventy unselected consecutive DTC patients treated with an ablative activity of radioiodine (30 mCi) after rhTSH administration were also investigated to evaluate the relationship between serum peak TSH levels, BMI, and the effectiveness of 131I ablation.

Serum TSH was measured using an ultrasensitive commercial immunometric assay method (Diagnostic Products Corp., Los Angeles, CA). The serum peak TSH was considered as the maximum level reached by serum TSH after rhTSH.

Statistical analysis

The effect of the rhTSH stimulus was studied by a time-average [area under the curve (AUC)] and time-independent (peak values) analysis. The AUC for TSH was calculated by a trapezoidal method (12).

Data are presented as means ± SD. Statistical analysis was performed using Mann-Whitney U, Kruskal-Wallis, and {chi}2 tests according to the data to be analyzed. Pearson correlation and stepwise forward multiple linear regression test were used to determine the independent effect of all parameters related to peak TSH levels. Statistical significance was defined as P < 0.05.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Correlation of anthropometric features and serum peak TSH after rhTSH in a selected group of normal-weight, overweight, and obese DTC patients

After rhTSH administration, a wide spectrum of values of serum peak TSH (mean, 95.7 ± 40.3 µU/ml; range, 43.1–237.0 µU/ml; median, 86 µU/ml.) was observed, with many of our patients (50 of 105 patients, 47.6%) showing a serum peak TSH between 40 and 75 µU/ml (63.1 ± 7.6 µU/ml; range, 43.1–74 µU/ml; median, 64 µU/ml).

As shown in Fig. 1AGo, we found a significantly lower value of peak TSH in overweight and obese with respect to normal-weight subjects (92.1 ± 41.8, 82.4 ± 24.2, and 112.7 ± 46.3 µU/ml, respectively; P = 0.01). The serum peak TSH was observed at d 3 (24 h after the second rhTSH injection) in 99 patients (94.3%) and at d 2 (24 h after the first rhTSH injection) in only six patients (5.7%). The time of the serum peak TSH did not show any difference between the three groups of patients.



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  		FIG. 1. Evidence of a statistically significant difference in serum peak TSH after rhTSH in normal-weight vs. overweight and obese patients (A) (P = 0.01, by Kruskal-Wallis statistical analysis) and in females (n = 73) vs. males (n = 32) (B) (P = 0.0002, by Mann-Whitney statistical analysis).

 
Serum peak TSH was significantly lower in males than females (74.6 ± 22.3 and 105.0 ± 43.0 µU/ml, respectively; P = 0.0002) (Fig. 1BGo). By univariate analysis, serum peak TSH was negatively related to height, weight, BSA, and BMI (Fig. 2Go, A–D). A significant negative correlation was found between serum peak TSH and the body composition. In particular, as shown in Fig. 2Go, E and F, both the LBM and FBM were negatively correlated with the values of serum peak TSH (r = 0.48, P < 0.007; and r = 0.24, P < 0.0001, respectively). However, by multivariate analysis, only LBM was independently associated with serum peak TSH levels (P < 0.0001)



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  		FIG. 2. Linear regression analysis between serum peak TSH after rhTSH and several anthropometric parameters [height (A), weight (B), BSA (C), BMI (D)] and body composition [LBM (E) and FBM (F)], showing evidence for an inverse relation among all analyzed parameters and serum peak TSH.

 
In agreement with these findings, also the TSH AUC was lower in overweight and obese patients with respect to normal-weight subjects (205 ± 86.9, 183 ± 48.4, and 234 ± 89.7 µU/ml·d, respectively; P < 0.05). The TSH AUC was also significantly lower in males than females (161.2 ± 42.2 and 227.9 ± 83.4 µU/ml·d, respectively; P < 0.0001).

By univariate analysis, TSH AUC was negatively related to height, weight, BSA, and BMI (r = 0.47, P < 0.0001; r = 0.39, P < 0.0001; r = 0.47, P < 0.001; and r = 0.24, P = 0.01, respectively). A significant negative correlation was also found between TSH AUC and the LBM (r = 0.50; P < 0.0001) but not between TSH AUC and FBM. As for the serum peak TSH, only LBM was independently associated with TSH AUC by multivariate analysis (P < 0.0001).

Relationship between serum peak TSH, BMI, and rhTSH 131I ablation rate in a group of consecutive DTC patients

The 70 patients treated with rhTSH for thyroid remnant ablation were distributed into three groups based on BMI: 34 normal-weight, 18 overweight, and 18 obese patients. As expected, also in the 70 DTC patients, serum peak TSH and TSH AUC were significantly lower in overweight and obese patients than in normal-weight patients (serum peak TSH was 120.7 ± 49.6, 99.1 ± 32.8, and 146.7 ± 38.5 µU/ml, respectively; P = 0.0006; TSH AUC was 213.2 ± 80.5, 173.2 ± 42.5, and 269.0 ± 70.0 µU/ml·d; P = 0.0009).

Although the percentage of thyroid remnant ablation obtained after one course of 131I was quite low (54%), the rate of ablation did not differ among normal-weight (48.5%), overweight (61.1%), and obese (61.1%) patients (P = 0.49), thus demonstrating that the lower levels of serum peak TSH observed in obese and overweight patients did not influence the rate of ablation.

Furthermore, serum peak TSH values and TSH AUC were not different between ablated and nonablated patients (123.9 + 44.8 µU/ml and 132.8 + 44.6 µU/ml, respectively; P = 0.40).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Recently, rhTSH administration has been introduced in the follow-up of patients affected by DTC as a valid alternative to the endogenous hypothyroidism obtained after L-T4 withdrawal (4, 5). However, at the present, the drug is approved only for diagnostic purposes such as Tg stimulus and 4- to 5-mCi 131I diagnostic whole-body scan. Promising results have been obtained in the multicentric randomized study regarding the possibility of using rhTSH for the thyroid remnant ablation (9), and an official approval of rhTSH for this purpose will be likely obtained in a few months.

It has been reported that among several anthropometric parameters (weight, height, BMI, and BSA) only BSA was independently and inversely associated with higher serum peak TSH levels after rhTSH administration (10). In this study, we demonstrated that when the LBM and FBM were analyzed together with several other parameters by multivariate analysis, LBM was the only variable in the model when a stepwise regression test was performed with all independent variables (sex, height, weight, BMI, BSA, FBM, and LBM). It is worth noting that also TSH AUC showed the same results as serum peak TSH, being lower in overweight and obese patients and correlating with LBM. Because rhTSH is a hydrophilic drug (11), our finding is in keeping with previous general observations suggesting that LBM is the most influencing physical parameter for the hydrophilic drugs dosage (1).

We also found that males had significantly lower values of serum peak TSH with respect to females. Based on the observation that LBM can negatively influence the serum peak TSH, the finding of a significantly higher serum peak TSH in men might be explained by the different body composition with a higher proportion of LBM in males than in females, which has been already demonstrated (13).

As a consequence of this evident relationship, the question whether the rhTSH dose should be personalized arises spontaneously. To answer this question, we reviewed the relationship between the serum peak TSH and the efficacy of 131I thyroid remnant ablation in 70 consecutive DTC patients treated with 131I after rhTSH for this purpose. Although the serum peak TSH was confirmed to be significantly lower in overweight and obese patients, we did not find any difference in the remnant ablation efficacy related to the serum peak TSH, thus suggesting that this is not the critical parameter influencing the rate of ablation. Other parameters such as the thyroid remnant volume, the effective half-life of radioactivity taken up by residual thyroid tumor after 131I therapy, or the initial dose rate delivered to the tissue might play a major role (14, 15, 16).

No adverse events after rhTSH administration were observed either in the 105 selected patients or in the 70 consecutive patients. In these series, the tumor mass expected was minimal or absent. rhTSH for Tg stimulus is indeed reserved to those patients with undetectable values of Tg on L-T4, and this prerequisite is rarely observed in patients with metastatic disease (17). However, by reviewing the published series of metastatic DTC patients treated with rhTSH (18, 19, 20) we found that three of 58 (5%) patients experienced severe side effects mainly related to the swelling of the tumor mass, thus suggesting that the dose of rhTSH might have to be personalized in those cases with a very advanced disease.

In conclusion, among weight, height, BMI, BSA, LBM, FBM, and sex, LBM is the only parameter independently associated with serum peak TSH after rhTSH administration. However, the serum peak TSH does not influence the rate of 131I remnant ablation, and the TSH levels usually obtained with the standard protocol are sufficient for the purpose.


   Footnotes
 
This study has been supported in part by grants from Ministero della Istruzione Universitaria e Ricerca Scientifica (MIUR) 2004 and Associazione Italiana per la Ricerca sul Cancro 2004. M.G.C. and E.M. are Ph.D. students in Endocrine and Metabolic Sciences. M.G.C. is a recipient of a Fondazione Italiana per la Ricerca sul Cancro fellowship.

First Published Online May 3, 2005

Abbreviations: AUC, Area under the curve; BMI, body mass index; BSA, body surface area; DTC, differentiated thyroid carcinoma; FBM, fat body mass; LBM, lean body mass; rh, recombinant human; Tg, thyroglobulin.

Received March 10, 2005.

Accepted April 27, 2005.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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