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

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.

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.