Association of Thyroid Hormone Therapy With Quality of Life and Thyroid-Related Symptoms in Patients With Subclinical Hypothyroidism: A Systematic Review and Meta-analysis

Abstract

Importance: The benefit of thyroid hormone therapy for subclinical hypothyroidism is uncertain. New evidence from recent large randomized clinical trials warrants an update of previous meta-analyses.

Objective: To conduct a meta-analysis of the association of thyroid hormone therapy with quality of life and thyroid-related symptoms in adults with subclinical hypothyroidism.

Data sources: PubMed, EMBASE, ClinicalTrials.gov, Web of Science, Cochrane Library, CENTRAL, Emcare, and Academic Search Premier from inception until July 4, 2018.

Study selection: Randomized clinical trials that compared thyroid hormone therapy with placebo or no therapy in nonpregnant adults with subclinical hypothyroidism were eligible. Two reviewers independently evaluated eligibility based on titles and abstracts of all retrieved studies. Studies not excluded in this first step were independently assessed for inclusion after full-text evaluation by 2 reviewers.

Data extraction and synthesis: Two independent reviewers extracted data, assessed risk of bias (Cochrane risk-of-bias tool), and evaluated the quality of evidence (GRADE tool). For synthesis, differences in clinical scores were transformed (eg, quality of life) into standardized mean differences (SMDs; positive values indicate benefit of thyroid hormone therapy; 0.2, 0.5, and 0.8 correspond to small, moderate, and large effects, respectively). Random-effects models for meta-analyses were applied.

Main outcomes and measures: General quality of life and thyroid-related symptoms after a minimum follow-up of 3 months.

Results: Overall, 21 of 3088 initially identified publications met the inclusion criteria, with 2192 adults randomized. After treatment (range, 3-18 months), thyroid hormone therapy was associated with lowering the mean thyrotropin value into the normal reference range compared with placebo (range, 0.5-3.7 mIU/L vs 4.6 to 14.7 mIU/L) but was not associated with benefit regarding general quality of life (n = 796; SMD, -0.11; 95% CI, -0.25 to 0.03; I2=66.7%) or thyroid-related symptoms (n = 858; SMD, 0.01; 95% CI, -0.12 to 0.14; I2=0.0%). Overall, risk of bias was low and the quality of evidence assessed with the GRADE tool was judged moderate to high.

Conclusions and relevance: Among nonpregnant adults with subclinical hypothyroidism, the use of thyroid hormone therapy was not associated with improvements in general quality of life or thyroid-related symptoms. These findings do not support the routine use of thyroid hormone therapy in adults with subclinical hypothyroidism.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Quinn reported being an investigator on one of the trials included in this review (funded by the European Union 7th Framework Program scheme) and also an investigator on an RCT in which the study drug was provided by Merck. Dr Stott reported receipt of a research grant from the European Union 7th Framework Program scheme. No other disclosures were reported.

Figures

Figure 1.. Randomized Clinical Trials of Levothyroxine Therapy in Subclinical Hypothyroidism Quality-of-Life and Mood-Related Outcomes

BDI indicates Beck Depression Inventory; EQ-5D, Euro Quality of Life 5 Dimensions Questionnaire; HADS, Hospital Anxiety and Depression Scale; ThyDQoL, 18-Item Underactive Thyroid-Dependent Quality of Life; ThyPRO, Thyroid-Related Quality-of-Life Patient-Reported Outcome Measure. Mean values of the quality-of-life and mood-related outcome scales per study group are shown in eTable 2 in Supplement 1. Weights are derived from a fixed-effects meta-analysis of standardized mean differences. Sizes of data markers indicate weight of studies. All effect sizes are standardized. Standardized mean differences of 0.2, 0.5, and 0.8 correspond to small, moderate, and large clinical effects, respectively. See Table for descriptions of outcome scales. Numbers differ between participants randomized and participants with available outcome data in the studies by Kong et al, Jorde et al, Reuters et al, Stott et al, and Meier et al (see Table and eTable 2). The study by Razvi et al is a crossover study that included 100 participants.

Figure 2.. Randomized Clinical Trials of Levothyroxine Therapy in Subclinical Hypothyroidism Outcomes on Cognitive Function

MMSE indicates Mini Mental State Examination. Mean values of the cognition scale per study group are shown in eTable 2 in Supplement 1. Weights are derived from a fixed-effects meta-analysis of standardized mean differences. Sizes of data markers indicate weight of studies. Dashed vertical line represents overall mean effect. All effect sizes are standardized. Standardized mean differences of 0.2, 0.5, and 0.8 correspond to small, moderate, and large clinical effects, respectively. See Table for descriptions of outcome scales. Numbers differ between participants randomized and participants with available outcome data in the studies by Jorde et al and Stott et al (see Table and eTable 2).

Figure 3.. Randomized Clinical Trials of Levothyroxine Therapy in Subclinical Hypothyroidism Outcomes on Systolic Blood Pressure

Weights are derived from a fixed-effects meta-analysis of differences in blood pressure. Sizes of data markers indicate weight of studies. Dashed vertical line represents overall mean effect. Numbers differ between participants randomized and participants with available outcome data in the study by Stott et al (see Table and eTable 2 in Supplement 1). The study by Razvi et al is a crossover study that included 100 participants.

Figure 4.. Randomized Clinical Trials of Levothyroxine Therapy in Subclinical Hypothyroidism Outcomes on Body Mass Index

Weights are derived from a random-effects meta-analysis of differences in body mass index (calculated as weight in kilograms divided by height in meters squared). Sizes of data markers indicate weight of studies. Dashed vertical line represents overall mean effect. Numbers differ between participants randomized and participants with available outcome data in the studies by Kong et al, Teixeira et al, and Stott et al (see Table and eTable 2 in Supplement 1). The study by Razvi et al is a crossover study that included 100 participants.