Importance: The standard of care for overt hypothyroidism is levothyroxine at doses that normalize serum TSH levels. This approach may not universally restore thyroid hormone signaling as patients have increased serum thyroxine-to-triiodothyronine ratios and may report residual symptoms.

Objective: To conduct a systematic review of studies of overt, primary hypothyroidism in which participants were treated with levothyroxine at doses that normalized serum TSH levels and measured other, objective markers of thyroid hormone signaling.

Data Sources: Five databases from inception to October 2017.

Study Selection: Studies that reported objective, systemic markers of thyroid hormone signaling in levothyroxine monotherapy for overt, primary hypothyroidism among nonpregnant adult humans with normal serum TSH levels were included.

Data Extraction and Synthesis: PRISMA guidelines were used to assess data quality and validity. For studies with serum cholesterol and sex hormone-binding globulin outcomes, data were pooled using random effects meta-analysis.

Main Outcomes and Measures: Serum low-density lipoprotein (LDL), total cholesterol (TC), sex hormone-binding globulin (SHBG), creatine kinase (CK) and/or ferritin levels; markers of cognition, energy expenditure, and renal function.

Results: A total of 99 studies were included in our review consisting of randomized trials, cohort, case-control, and cross-sectional studies, small series and case reports including 65 studies that reported serum cholesterol levels. Meta-analysis showed that levothyroxine-treated hypothyroid participants with normal serum TSH levels had 3.31 ± 1.64 mg/dL higher serum LDL levels (p=0.044) and 9.60 ± 3.55 mg/dL higher serum TC levels (p=0.007) compared to healthy controls. In studies that did not concomitantly assess healthy controls, serum LDL levels were 138.3 ± 4.6 mg/dL (p<0.001) and serum TC levels were 209.6 ± 3.4 mg/dL (p<0.001). Meta-analysis of 2 studies showed no significant difference between the SHBG levels of levothyroxine-treated participants and healthy controls. There were too few data available and/or limitations due to study heterogeneity to perform meta-analysis of data including cognition, energy expenditure, renal function, CK and ferritin. Conclusions and Relevance: In studies that utilized levothyroxine monotherapy at doses that normalized the serum TSH for overt, primary hypothyroidism, not all systemic biological markers of thyroid hormone signaling were normalized, including serum LDL and TC levels.

Systemic Thyroid Hormone Status During Levothyroxine Therapy In Hypothyroidism: A Systematic Review and Meta-Analysis.

EA McAninch, KB Rajan, CH Miller, AC Bianco. J Clin Endocrinol Metab. 2018 Aug 15. PMID: 30124904

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