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There have been recent advances in understanding of the local control of thyroid activity and metabolism, including deiodinase activity and thyroid hormone membrane transport. The goal of this review is to increase the understanding of the clinical relevance of cellular deiodinase activity. The physiologic significance of types 1, 2 and 3 deiodinase (D1, D2 and D3, respectively) on the intracellular production of T3 are discussed along with the importance and significance of the production of reverse T3. The difference in the pituitary and peripheral activity of these deidoidinases under a wide range of common physiologic conditions results in different intracellular T3 levels in the pituitary and peripheral tissues, resulting in the inability to detect low tissue levels of thyroid hormone in peripheral tissues with TSH testing. This review demonstrates that extreme caution should be used in relying on TSH or serum thyroid levels to rule out hypothyroidism in the presence of a wide range of conditions, including physiologic and emotional stress, depression, dieting, obesity, leptin insulin resistance, diabetes, chronic fatigue syndrome, fibromyalgia, inflammation, autoimmune disease, or systemic illness, as TSH levels will often be normal despite the presence of significant hypothyroidism. The review discusses the significant clinical benefits of thyroid replacement in such conditions despite having normal TSH levels and the superiority of T3 replacement instead of standard T4 therapy.

Peripheral Thyroid Hormone Conversion and Its Impact on TSH and Metabolic Activity