Metabolic Effects of Synthetic Thyroid Hormone for Thyroid Cancer Treatment
Metabolic Effects of Synthetic Thyroid Hormone for Thyroid Cancer Treatment
Background:

 - Thyroid hormone is produced by the thyroid gland, an organ at the base of the neck. Thyroid
 hormone controls the body's metabolism and the function of many organs. The thyroid gland
 produces two forms of thyroid hormone: T4 and T3. People who have thyroid cancer are treated
 with thyroid hormone therapy (synthetic T4, levothyroxine), which at times needs to be
 stopped to allow for cancer treatments. At these times, a different form of thyroid hormone
 (synthetic T3, liothyronine) is used to reduce the symptoms caused by low levels of thyroid
 hormone. Researchers want to know more about how changes in T3 hormone affect the body and
 organ function.

 Objectives:

 - To study how changes in T3 hormone levels affect the body and organ function.

 Eligibility:

 - Individuals at least 18 years of age who have had most or all of their thyroid removed to
 treat thyroid cancer who need to stop taking their regular thyroid hormone dose in
 preparation for the treatment of thyroid cancer.

 Design:

 -  The study involves a screening visit and a baseline evaluation. It also includes an
 11-day inpatient hospital stay.

 -  Participants will be screened with a physical exam and medical history. They will also
 have blood tests and a neck ultrasound.

 -  Participants will be evaluated with a physical exam, blood tests, and the following
 procedures:

 -  Glucose tolerance test to measure blood sugar

 -  Tests of body fat, muscle strength, and calorie burning levels

 -  Imaging studies of the heart, liver, and thigh muscles

 -  Quality of life questionnaires

 -  Food preference and diet questionnaires

 -  After 4 weeks of treatment with T3 hormone, participants will have an 11-day inpatient
 hospital stay to study the effect of thyroid hormone on their metabolism. The stay will
 involve the same tests done in the baseline evaluation.
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)