Thyroxine Titration Study
Thyroxine Titration Study
The aim of the study is to examine the effects of fine titration of thyroxine dosage on
 symptoms of hypothyroidism, wellbeing and quality of life. The hypothesis is that symptoms of
 hypothyroidism, wellbeing and quality of life will be improved in thyroxine-treated subjects
 when serum thyrotropin (TSH) is suppressed and/or in the lower reference range, compared to
 when TSH is in the upper reference range.
Primary hypothyroidism is a common disorder, affecting 2% of the Australian population. The
 standard treatment is with thyroxine (T4), and conventionally, a serum thyrotropin (TSH)
 concentration within the laboratory range is taken as indicating adequacy of thyroxine
 dosage.

 Some patients with hypothyroidism complain of persistently impaired well-being, despite
 taking thyroxine in a dose which normalises serum TSH concentrations. It is not clear whether
 this is because of comorbidity or because standard thyroxine replacement is in some way
 inadequate for some individuals.

 The reference range for serum TSH is wide (currently 0.34-4.8 mU/L at PathCentre). The
 distribution of serum TSH concentrations in the population is skewed, with the mean and
 median in the lower reference range at approximately 1.0 mU/L. This has led some to argue
 that a serum TSH in the lower reference range should be the usual therapeutic target.
 Anecdotal evidence suggests that some thyroxine-treated patients do feel better if the
 thyroxine dose is adjusted so that serum TSH is in the lower reference range rather than the
 upper reference range. The National Academy for Clinical Biochemistry of the United States
 now recommends, that for thyroxine-treated patients, that serum TSH should be less than 2.0
 mU/L. There is, however, no evidence from properly conducted studies that aiming for a serum
 TSH concentration in the lower reference range improves symptoms of hypothyroidism or general
 wellbeing, and this proposal has not been generally adopted.

 Only one study examining the effects of fine titration of thyroxine dosage on wellbeing has
 been published. In this study, patients had significantly improved wellbeing if they took a
 dose of thyroxine which was 50 μg greater than their biochemically optimal dose as determined
 by a thyrotropin-releasing hormone test. In most cases, serum TSH was suppressed to below 0.2
 mU/L (the limit of sensitivity of the assay) on the thyroxine doses which improved wellbeing.
 This study was open-label and non-randomised, and the results therefore may have been
 affected by bias.

 A well-designed, double blind study of the effects of fine titration of thyroxine dosage on
 symptoms of hypothyroidism, wellbeing and quality of life is required to determine if a serum
 TSH in the lower reference range, rather than simply TSH within the reference range, should
 indeed be the usual therapeutic target for thyroxine therapy in primary hypothyroidism. It is
 also desirable to confirm the findings of Carr et al., that patients have improved wellbeing
 if TSH is suppressed to below normal levels.
Inclusion Criteria:

 -  Male or female subjects >18 years of age

 -  Primary hypothyroidism ≥6 months duration arising from autoimmune hypothyroidism,
 thyroidectomy or radioiodine treatment

 -  Thyroxine dose ≥100 mcg/day

 -  No change in thyroxine dose in past 2 months

 -  Serum TSH of 0.1-4.8 mU/L

 -  Adequate contraceptive measures for women of childbearing age

 Exclusion Criteria:

 -  Major systemic illness affecting quality of life or likely to affect participation in
 the study

 -  Treatment with T3 currently or in past 2 months

 -  History of thyroid cancer requiring suppression of TSH secretion by thyroxine

 -  Ischaemic heart disease - previous myocardial infarction, angina or coronary artery
 revascularisation

 -  Renal failure: serum creatinine >135 micromol/L

 -  Known liver disease with alkaline phosphatase or ALT >2x upper limit of reference
 range

 -  Bony fracture in past 3 months or Paget's disease of bone

 -  Secondary (central) hypothyroidism or hypopituitarism