Clinical, behavioural and pharmacogenomic factors influencing the response to levothyroxine therapy in patients with primary hypothyroidism—protocol for a systematic review

Abstract

BackgroundSuboptimal 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/designThe 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.DiscussionThis 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.Systematic review registrationPROSPERO CRD42015027211 Electronic supplementary materialThe online version of this article (doi:10.1186/s13643-017-0457-z) contains ...

Hypothyroidism in Context: Where We’ve Been and Where We’re Going

“…Hypothyroidism is also associated with decreased quality of life, most likely related to symptoms such as changes in body weight, fatigue, weakness and depression [1, 12, 17–19]. Physicians and patients themselves rate fatigue and emotional susceptibility as being particularly relevant to the impact of hypothyroidism [51].…”

“…Despite the switch to levothyroxine monotherapy in the 1970s [65], the need for combination therapy with levothyroxine + LT3 has been recently readdressed in several clinical guidelines [13, 75, 76]. More than a third of patients remain inadequately treated despite levothyroxine therapy, with evidently elevated TSH levels and/or persistent symptoms [12, 13]. Even when TSH levels are controlled on levothyroxine, about 5–10% of treated hypothyroid patients have persistent symptoms for various reasons [76], including differences in individual set-points, coexistence of other autoimmune diseases, and failure to appropriately convert T4 to T3 with a low T3/T4 ratio, on levothyroxine monotherapy.…”

“…Hypothyroidism affects up to 5% of the population according to European prevalence estimates [8–11], while as many as 5% of the population may have undiagnosed thyroid failure [9]. Of patients who are treated, up to one-third are not receiving adequate treatment [12, 13]. The economic impact of undiagnosed, untreated or undertreated hypothyroidism is therefore not inconsequential, especially with regard to costs associated with maternal and congenital hypothyroidism [14, 15], or with hypothyroid patients having comorbid conditions such as diabetes mellitus [16].…”

“…The economic impact of undiagnosed, untreated or undertreated hypothyroidism is therefore not inconsequential, especially with regard to costs associated with maternal and congenital hypothyroidism [14, 15], or with hypothyroid patients having comorbid conditions such as diabetes mellitus [16]. Hypothyroidism is also associated with decreased quality of life [1, 12, 17–19], increased number of sick leave days [20], and even increased mortality [21].…”

Incidences of Hypothyroidism Associated With Surgical Procedures for Thyroid Disorders: A Nationwide Population-Based Study

“…While medical therapy with an anti-thyroid drug is commonly adopted in European nations and Japan as the first-choice method of therapy, the disease still often occurs. Recent systematic review reported the clinical, behavioral and pharmacogenomic factors could be influence in response to levothyroxine therapy in patients with primary hypothyroidism (Dew et al, 2017).…”