Thyroid and Glucose and Energy Metabolism
Thyroid and Glucose and Energy Metabolism
This study will examine how two thyroid preparations-levothyroxine (T4) and liothyronine
 (T3)-affect fat and cholesterol metabolism, blood sugar regulation, and thyrotropin secretion
 in patients who have had their thyroid gland removed. Results of the study may help in the
 development of better therapies to optimize blood sugar and cholesterol levels in some
 patients.

 Patients 18 years of age or older who have had most or all of their thyroid gland removed and
 are taking long-term thyroid hormone medication may be eligible for this study after
 screening.
Thyroid hormone action plays an important role in the regulation of many physiologic
 processes, among them glucose and lipid metabolism. Interestingly, the clinical presentation
 of thyroid dysfunction is extremely variable, with relatively poor correlation between
 circulating hormone levels and clinical features. This finding suggests that the local,
 intracellular concentration of the active hormone liothyronine (T3), regulated by peripheral
 conversion of the pro-hormone levothyroxine (T4), is an important determinant in the
 maintenance of the thyroidal homeostasis.

 The aim of the present study is the evaluation of the role of peripheral thyroid hormone
 conversion in the regulation of glucose and lipid metabolism by assessing the differential
 response to T4 or T3 treatment in subjects devoid of endogenous thyroid hormone production.
 T3 administration bypasses peripheral metabolism and therefore will allow us to assess the
 role of the peripheral thyroid hormone conversion in the regulation of the hormone action at
 the end-organ level.

 Fifty hypothyroid subjects will be initially randomized to either of the thyroid hormone
 replacements liothyronine (T3) or levothyroxine (T4) treatment period (one arm cross-over
 design, with treatment sequence randomized), aimed to maintain serum TSH levels greater than
 or equal to 0.5 less than or equal to 1.5 mU/L, indicating full replacement. After a 30-day
 period of steady-state replacement the study subjects will be admitted to the Clinical Center
 and, after a three-day period of stabilization and an overnight fast, will undergo the
 following tests: escalating dose TRH stimulation test, indirect calorimetry, graded exercise
 tolerance test, DEXA scan, and echocardiogram.

 Patients will also undergo skeletal muscle biopsy and subcutaneous adipose tissue biopsy and
 microdialysis, as well as a two-step euglycemic hyperinsulinemic clamp with measurement of
 splanchnic gluconeogenesis. Fasting venous blood samples will be collected for the
 determination of the parameters of lipid, glucose and energy metabolism.

 After discharge, the patients will switch to the other form of thyroid hormone replacement
 therapy (second period) . The therapy will be adjusted in order to achieve the same
 therapeutic goal for TSH concentrations (greater than or equal to 0.5 less than or equal to
 1.5 mU/L), analogous to that achieved during the first phase of the study (TSH less than or
 equal to 0.5 mU/L difference between T3 and T4 phases). After reaching a 30-day period of
 steady-state replacement, study subjects will be re-admitted to the Clinical Center and the
 previously described evaluation procedures will be repeated.
-  INCLUSION CRITERIA:

 Age greater than or equal to 18 years, male or female.

 History of total or near total thyroidectomy or hypothyroidism on replacement therapy.

 For non-thyroidectomized patients, at least three-year history of replacement therapy (at
 least 1.2 mcg/Kg LT4/body weight), and less than 5% uptake at 24H on (123)I thyroid scan
 while on replacement therapy.

 Written informed consent.

 EXCLUSION CRITERIA:

 BMI less than or equal to 20 or greater than or equal to 30 kg/m(2).

 Metastatic thyroid cancer or history of thyroid cancer with high risk of recurrence
 requiring suppressive thyroid hormone therapy (Singer 1996).

 Significant thyroid residual greater than 1 mL as measured by ultrasound (limited to
 thyroidectomized patients) or greater than 5 percent uptake at 24H on (123)I thyroid scan
 while on replacement therapy (limited to hypothyroid patients not undergone total
 thyroidectomy).

 History or symptoms compatible with cardiovascular disease, including paroxysmal
 supraventricular tachycardia, atrial fibrillation, syncopal episodes or use of prescription
 medications for heart conditions, including antihypertensives.

 Allergy to lidocaine, isoproterenol, TRH, levothyroxine, liothyronine, Tylenol #3,
 oxycodone, nitroglycerin.

 Pregnancy or unwillingness to use non-hormonal contraception during the study.

 Breastfeeding

 Use of hormonal contraceptives or estrogen replacement therapy.

 Use of tobacco (smoking, chewing) for the two weeks preceding the hospital admissions
 (metabolic testing)

 Diabetes mellitus, either type I or II.

 Hypercholesterolemia (serum levels greater than or equal to 240 mg/dL),
 hypertriglyceridemia (plasma levels greater than or equal to 220 mg/dL) and/or use of
 antilipemic therapy.

 Liver disease or ALT serum level greater than two fold the upper laboratory reference
 limit.

 Renal insufficiency or estimated creatinine clearance less than or equal to 50 mL/min.

 Use of medications/supplements/alternative therapies known to alter thyroid function.

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

 Use of antipsychotic medications

 History of drug or alcohol abuse within the last 5 years; current use of drugs or alcohol
 (CAGE greater than 3).

 Keloid formation (relative to skeletal muscle and subcutaneous adipose tissue biopsies).

 Current or previous clinically significant (requiring medical/surgical intervention)
 extrathyroidal manifestations of autoimmune thyroid disease (dermopathy, ophthalmopathy,
 arthropathy).