Metabolic Effects of Synthetic Thyroid Hormone for Thyroid Cancer Treatment

In human adults thyroid hormone action plays a critical role in the modulation of metabolism
and the function of virtually all organ/systems. The specificity of the hormonal action is
ultimately the result of the interaction of the active hormone, triiodothyronine (T3), with
the receptors isoforms and the co-activators and co-repressors specific for the various cells
target of the hormonal action. Circulating and tissue levels of T3 are the result of the
secretion of T3 and its precursor, thyroxine (T4), from the thyroid gland, the peripheral
conversion of T4 into T3, and the degradation of these hormones. This complex system has only
been partially studied in humans and very little is known regarding the kinetics of T3, and
in particular on the correlation between circulating levels of T3 and end-organ target tissue
thyroid hormone action.

The aim of this protocol is to characterize the pharmacokinetics of T3 and its biological
effects at various concentrations in a cohort of thyroidectomized patients undergoing thyroid
hormone replacement therapy withdrawal for the management of thyroid cancer.

Sixteen patients with a clinical indication for thyroid hormone withdrawal in preparation for
131I therapy or 123I diagnostic scan for follow-up and management of differentiated thyroid
cancer will be recruited for this study. After enrollment in the study, the patients baseline
characteristics will be determined during an outpatient visit while receiving levothyroxine
(L-T4) therapy. The L-T4 therapy then will be suspended and substituted with an equivalent
thrice daily liothyronine (L-T3) therapy for one month. Patients will be admitted to the NIH
Clinical Center on the day prior to withdrawal of the T3 therapy until the diagnostic scan or
the administration of radioactive iodine. During the hospitalization for this research
protocol, which is expected to last eleven days, the following studies will be performed:
serial blood sampling for circulating thyroid hormones to obtain pharmacokinetic parameters
of L-T3, lipids, glucose and insulin, resting energy expenditure, echocardiogram, skeletal
muscle strength measurement, cardiac, hepatic and skeletal muscles MRI, and quality of life
and well-being questionnaires. The pharmacokinetic parameters of L-T3 will also be assessed
with the first dose after the diagnostic scan or the administration of radioactive iodine.

The results obtained from this study will help in understanding the effects of thyroid
hormone on metabolism, and may lead to important information on how to optimize the duration
of the thyroid hormone therapy withdrawal for the treatment of thyroid cancer.

- INCLUSION CRITERIA:

Subjects will be adult volunteers older than age 18 who underwent total thyroidectomy for
the treatment of differentiated thyroid cancer, previously undergone radioactive iodine
ablation of the thyroid gland remnant, with clinical indication for withdrawal from thyroid
hormone replacement therapy in preparation for nuclear medicine imaging or therapeutic
procedures with radioactive iodine. The patient population will be recruited from the
participants in the 77-DK-0096 natural history protocol: Studies on Thyroid Nodules and
Thyroid Cancer , PI Dr.Joanna Klubo-Gwiezdzinska and from the 10-C-0102 natural history
protocol: Clinical and Genetic Studies in Familial Non-Medullary Thyroid Cancer , PI
Electron Kebebew.

EXCLUSION CRITERIA:

1. Significant thyroid residual greater than 5 gm as measure by ultrasound or greater
than 5 percent uptake at 24 H on (123) I pre-treatment thyroid scan.

2. Renal insufficiency or estimated creatinine clearance less than or equal to 60
mL/min/1.73M(2) BSA by MDRD equation before thyroid hormone withdrawal.

3. Liver disease or ALT >2.5 times the upper laboratory reference limit.

4. Pharmacologic therapy for the treatment of psychiatric conditions.

5. History of, and/or current coronary artery disease.

6. Current history or symptoms compatible with psychosis or major depression (including
history of hospitalization for depression, history of attempted suicide, history of
suicidal ideation). Use of antipsychotic medications.

7. History of drug or alcohol abuse within the last year; current use of illicit drugs or
alcohol abuse (CAGE>3).

8. Pregnancy (women of child-bearing potential must have a negative pregnancy test prior
to inclusion) or use of hormonal contraceptives.

9. Known allergy to L-T3.

10. Current use of prescription medication or certain non-prescription medications and
dietary supplements known to affect thyroid function and/or metabolism, or alter the
pharmacokinetics of L-T3.

11. Inability or unwillingness to follow the low-iodine, metabolic diet or non-compliance
to the L-T3 administration regimen.

12. The presence of persistent diarrhea or malabsorption syndromes that would interfere
with the patient s ability to adequately absorb drugs.

13. Inability to obtain venous access for sample collection, or basal hemoglobin of less
than or equal to 10 g/dL.

14. Low functional status (ECOG Performance Status > 2)