Systemic Thyroid Hormone Status during Levothyroxine Therapy in Hypothyroidism: A Systematic Review and Meta-Analysis

Context: The standard of care for overt hypothyroidism is levothyroxine (LT4) at doses that normalize serum TSH levels. Whether this approach universally restores thyroid hormone signaling is unknown. Objective: To review studies of overt hypothyroidism in which participants received LT4 to normalize serum TSH levels and measure other objective markers of thyroid hormone signaling. Design: Databases were searched for studies that reported objective markers of thyroid hormone signaling [serum low-density lipoprotein (LDL), total cholesterol (TC), SHBG, creatine kinase and/or ferritin levels; cognition, energy expenditure, and/or renal function] during LT4 monotherapy for overt, primary hypothyroidism among nonpregnant adults with normal serum TSH levels. For studies with LDL, TC, and SHBG outcomes, the data were pooled using random effects meta-analysis. Results: A total of 99 studies met the inclusion criteria, including 65 reporting serum cholesterol data. The meta-analysis showed that LT4-treated participants with hypothyroidism but normal serum TSH levels had 3.31 ± 1.64 mg/dL greater serum LDL (P = 0.044) and 9.60 ± 3.55 mg/dL greater serum TC (P = 0.007) compared with controls. In studies that had not concomitantly assessed healthy controls, serum LDL was 138.3 ± 4.6 mg/dL (P < 0.001) and serum TC was 209.6 ± 3.4 mg/dL (P < 0.001). A meta-analysis of two studies showed no important differences between the SHBG levels of LT4-treated participants and controls. Conclusions: In studies of LT4 monotherapy at doses that normalized serum TSH for overt, primary hypothyroidism, not all systemic biological markers of thyroid hormone signaling were normalized, including the serum LDL and TC levels.