The Role of Thyroid Status in Regulating Brown Adipose Tissue Activity, White Adipose Tissue Partitioning and Resting Energy Expenditure (TRIBUTE)

To determine how thyroid status regulates the relationship between brown adipose tissue (BAT) volume/activity, white adipose tissue (WAT) partitioning and basal metabolic rate (BMR) in hyperthyroid patients transitioning to euthyroidism via antithyroid drugs.

To compare euthyroid outcomes (BAT, WAT, BMR, body composition, body weight and insulin resistance) achieved by hypothalamus-pituitary-thyroid (HPT) set point vs. normal ranges of plasma free thyroxine 4 (FT4) and throxine stimulating hormone (TSH).

Study Overview

• Status: Completed
• Conditions: Hyperthyroidism
• Intervention / Treatment: Drug: carbimazole (CMZ) or thiamazole (TMZ)

Detailed Description

Study Visit 1 is meant to confirm if subject's hyperthyroidism is due to Graves' disease via a blood test called TSH receptor autoantibody (TRAb). This is a standard test that the doctor will routinely order as part of clinical practice to diagnose the cause of the subject's hyperthyroidism and is not part of the research procedure. If this TRAb blood test has been done before the subjects have been referred to the endocrinology clinic at TTSH, the doctors will review that result and decide if a repeat test is needed. If subjects are confirmed by blood tests to have Graves' disease type of hyperthyroidism, they are eligible to take part in this study. However, approximately 2 teaspoons (~ 10 mL) of blood will be taken for baseline thyroid function test just prior to the initiation of anti-thyroid drugs. Pre-menopausal women will also undergo a urine pregnancy test to exclude pregnancy prior to participation at study entry. Once subjects have consented to participate in this study, they will receive standard antithyroid drug (ATD) therapy as indicated clinically which in current practice will either be carbimazole (CMZ) or thiamazole (TMZ).The clinic endocrinologists at TTSH will be in charge of deciding on the ATD dose required based on the latest FT4, FT3 and TSH blood test results as per standard medical practice. . Subjects will then be scheduled for Visit 2 for baseline research measurements while you are still hyperthyroid.

On Study Visit 2, subjects will be asked to come to the Clinical Nutrition Research Centre (CNRC) at the Centre for Translational Medicine at the National University of Singapore in the morning at 0830 h after an overnight fast of 8-10 hours. Subjects will undergo anthropometry (ie. measures of body weight, height, waist and hip circumference), non-invasive percentage fat estimation using bioelectrical impedence analysis (BIA) and body composition evaluation using dual energy X-ray absorptiometry (DXA) which allows quantification of fat, lean and bone mass. Subjects will then undergo metabolic rate measurement in a whole body calorimeter coupled with infrared thermography using a thermal camera mounted on a tripod stand (IRT) focusing on the neck and area above the collar bone in a whole body room calorimeter for the next 45 minutes.

Subjects will then proceed to the Clinical Imaging Research Centre (CIRC) also located in the same building at the basement where an intravenous indwelling cannula will be inserted into an arm vein from which a fasting blood sample will be taken. At first, 30 mL of blood will be taken (about 6 teaspoons) in which 10 mL will be tested for thyroid function while the other 10 mL will be tested for liver and kidney function and the remaining 10mL for fasting glucose, insulin and lipids. An additional 20 mL blood (about 4 teaspoons) will be taken for analysis of markers of fat metabolism and protein profiles reflective of brown fat activity. A urine sample will also be collected. Subsequently, subjects will be given an intravenous injection of a radioactive labeled glucose called 18-FDG through the intravenous cannula and followed by PET and fat fraction MRI scanning for BAT and MRI-MRS of abdominal white fat for the next 1 hour.

After that, subjects will then be required to go to the endocrinology clinic at TTSH for control of their hyperthyroidism via ATD. This may take about 6 months to attain stable thyroid hormones levels (FT4, FT3, TSH). Subjects will be followed up every 6-8 weeks as per standard medical practice by theTTSH endocrinologist and have their ATD doses adjusted till their thyroid function tests are stable'. When this happens, subjects will continue with the remaining part of the research, which is Study Visit 3. With the exception an additional urine pregnancy test, Study Visit 3 is exactly the same as Study Visit 2.

• Study Type: Observational
• Enrollment (Actual): 30

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 308433
    • Tan Tock Seng Hospital, Endocrinology Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 50 years (Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Hyperthyroid patients diagnosed with Graves' disease

Description

Inclusion Criteria:

• You must be aged 21 to 50 years old (no gender restrictions).
• You must be diagnosed with Graves' disease.
• You are able to give informed consent..
• You must have body mass index (BMI) between 18.5 to 29.9 kg/m2 inclusive.
• You must be treated with carbimazole (CMZ) or thiamazole (TMZ) and compliant to treatment.
• Willing to avail yourself for the whole study and follow study procedures.

Exclusion Criteria:

• Chronic illnesses such as diabetes mellitus or cancer.
• You have a known history of liver or kidney disease.
• Female subjects who are pregnant or contemplating pregnancy.
• Those allergic to carbimazole (CMZ) or thiamazole (TMZ).
• History of surgery with metallic clips, staples or stents.
• Those on drugs that might affect body composition (eg. steroids) or BAT (eg. beta-blockers).
• Those with poor compliance to medication.
• Presence of cardiac pacemaker or other foreign body in any part of the body.
• History of claustrophobia particularly in a MRI scanner.
• Those with a history of bronchial asthma.
• Those with overt congestive heart failure.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Other

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Thyroid function test (serum free thyroxine (FT4) and serum thyroid stimulating hormone (TSH).	This observation supports the concept of a unique set point in FT4 and TSH for any given individual and forms the basis for optimization of thyroid status by targeting the FT4 and TSH levels towards the set point. All data, study and clinical endpoints will be analyzed and correlated by the proximity of the final stable euthyroid Thyroid function test (TFT) to the predicted euthyroid set point using the computer software.	6 months of treatment with an anti-thyroid drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fat volume- Brown adipose tissue (BAT)	The above volumes will be measured at start of treatment and at 6 months by MRI (fat fraction for BAT) - volumes in mL.	6 months of treatment with an anti-thyroid drug
Fat volume- White adipose tissue (WAT)	The above volumes will be measured at start of treatment and at 6 months by MRI (standard MRI for WAT) - volumes in mL.	6 months of treatment with an anti-thyroid drug
Energy expenditure	The metabolic rate (measured from the energy expenditure) will be measured using the whole body calorimeter in kcal/day.	6 months of treatment with an anti-thyroid drug
Body composition	The subjects will have a body composition evaluated by DXA at the start of treatment and 6 months post-treatment when they are rendered euthyroid. WE will measure lean mass, fat mass and bone mass.	6 months of treatment with an anti-thyroid drug
Infrared thermography (IRT)	We will measure BAT activity using IRT. This will be expressed in terms of temperature change in degrees Celsius and heat power change in watts (W).	6 months of treatment with an anti-thyroid drug

Collaborators and Investigators

• Sponsor: Clinical Nutrition Research Centre, Singapore
• Collaborators: Agency for Science, Technology and Research

Publications and helpful links

General Publications

• Sun L, Goh HJ, Verma S, Govindharajulu P, Sadananthan SA, Michael N, Henry CJ, Goh JP, Velan SS, Leow MK. Brown adipose tissues mediate the metabolism of branched chain amino acids during the transitioning from hyperthyroidism to euthyroidism (TRIBUTE). Sci Rep. 2022 Mar 7;12(1):3693. doi: 10.1038/s41598-022-07701-7.

Study record dates

Study Major Dates

• Study Start (Actual): October 13, 2015
• Primary Completion (Actual): May 19, 2023
• Study Completion (Actual): May 19, 2023

Study Registration Dates

• First Submitted: February 9, 2017
• First Submitted That Met QC Criteria: February 21, 2017
• First Posted (Actual): February 27, 2017

Study Record Updates

• Last Update Posted (Actual): May 25, 2023
• Last Update Submitted That Met QC Criteria: May 24, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Thyroid Diseases; Hyperthyroidism; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Antithyroid Agents; Carbimazole
• Other Study ID Numbers: 2015/00718

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No