Abstract

Background
Suboptimal thyroid hormone therapy including under-replacement and over-replacement is common amongst patients with hypothyroidism. This is a significant health concern as affected patients are at risk of adverse cardiovascular or metabolic consequences. Despite a growing body of evidence on the effects of various factors on thyroid hormone replacement, a systematic appraisal of the evidence is lacking. This review aims to appraise and quantify the extent to which clinical, behavioural and pharmacogenomic factors affect levothyroxine therapy in patients with primary hypothyroidism.

Methods/Design
The databases Web of Science, Cochrane Library, EMBASE, and PubMed will be searched. Patients must be adults over the age of 18 years, suffering from primary hypothyroidism including overt and subclinical hypothyroidism, and receiving levothyroxine treatment. Studies in children, pregnant women, and patients with secondary or tertiary hypothyroidism will not be included. We will also exclude studies focused on forms of thyroid hormone replacement therapy other than levothyroxine.

The primary outcome is to quantify the effect of clinical, behavioural and pharmacogenomic factors on thyroid stimulating hormone (TSH) levels. Secondary outcomes are the effect these factors have on Thyroxine (T4) and Triiodothyronine (T3) levels, mortality, morbidity, quality of life, treatment complications, adverse effects, physical and social functioning. Studies will be screened through reading the title, abstract, and then full text. Two reviewers will independently extract the data and select articles, and a third reviewer will be consulted if there is any disagreement. We will undertake a meta-analysis of studies in which there is a defined intervention or exposure, patients are receiving levothyroxine for hypothyroidism, there is an appropriate control group of levothyroxine treated patients that are not exposed to the intervention, and the primary outcome is determined by serum TSH levels. Studies will comprise of randomised controlled trials as well as observational data.

Eligible studies will be assessed for bias using the risk of bias tool available in the Cochrane Handbook 2011, and the quality of evidence will be judged according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. A flow diagram describing the data search will be created according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis: The PRISMA Statement. A narrative synthesis will be undertaken in the description of the data, and summary tables will be created of the results.

Discussion
This review will be the first systematic review of this nature. The evidence synthesised will be useful to general practitioners in their management of hypothyroidism. Findings will be disseminated at conferences and in professional and peer-reviewed journals.