Mechanisms of Lithium-Induced Thyroid Dysfunction
Primary Cellular and Molecular Mechanisms
Lithium interferes with thyroid hormone synthesis and release through multiple biochemical pathways, with the most clinically significant effect being direct inhibition of thyroid hormone secretion from the gland. 1, 2, 3
Direct Effects on Thyroid Hormone Synthesis and Release
- Lithium is concentrated in the thyroid gland at 3-4 fold higher levels than plasma concentrations, creating a local toxic environment that disrupts normal thyroid function 4
- The drug inhibits thyroidal iodine uptake by interfering with the sodium-iodide symporter mechanism, reducing the raw substrate available for hormone synthesis 3
- Lithium blocks iodotyrosine coupling, the critical step where iodinated tyrosine residues combine to form T3 and T4 hormones 3
- Most importantly, lithium directly inhibits thyroid hormone secretion from the gland, which is the primary mechanism leading to clinical hypothyroidism and goiter development 3, 4
- The drug alters thyroglobulin structure, disrupting the normal storage and processing of thyroid hormones within the follicular colloid 3
Effects on Cellular Signaling and Enzyme Systems
- Lithium inhibits adenosine triphosphatase (ATPase) activity and cyclic AMP (cAMP) production, disrupting the normal cellular response to TSH stimulation 3
- The drug's inhibitory effect on inositol phospholipid metabolism affects intracellular signal transduction pathways that regulate thyroid hormone synthesis 3
- Lithium decreases peripheral deiodination of T4 to T3 by inhibiting type I 5'-deiodinase enzyme activity, reducing the conversion of the prohormone T4 to the more active T3 2, 3
- Effects on brain deiodinase enzymes and alterations in thyroid hormone receptor concentration in the hypothalamus may contribute to both therapeutic effects and thyroid dysfunction 3
Compensatory Response and Goiter Formation
- When lithium inhibits thyroid hormone release, TSH levels rise as the pituitary attempts to compensate, stimulating thyroid growth and leading to goiter formation 2, 3
- This compensatory mechanism explains why goiter occurs in 0-60% of patients (with wide variation in reported incidence) and is typically smooth and nontender 3
- The hypothalamic-pituitary axis adjusts to a new set point in patients receiving lithium, with 50-100% showing exaggerated TSH and prolactin responses to TRH stimulation 3
Autoimmune Mechanisms
- Lithium augments B lymphocyte activity and reduces the ratio of circulating suppressor to cytotoxic T cells, increasing susceptibility to thyroid autoimmunity 2, 4
- The drug increases antithyroid antibody titers in patients who already have these antibodies before starting treatment, but does not induce antibody synthesis de novo 3
- This autoimmune effect explains why hypothyroidism is usually associated with circulating anti-thyroid peroxidase (TPO) antibodies, though it can occur in their absence 3
- Middle-aged females (≥50 years), patients with family history of thyroid disease, and those positive for thyroid autoantibodies are at highest risk for developing lithium-induced thyroid dysfunction 2
Clinical Implications and Monitoring
- Subclinical and clinical hypothyroidism are the most prevalent thyroid abnormalities, with mean delay from starting lithium to requiring thyroid replacement therapy of 2.3 years (though 50% require treatment within 10 months) 2, 5
- Lithium-induced hypothyroidism appears reversible in approximately 41% of patients after lithium discontinuation, with only 6% requiring reinstatement of thyroid replacement therapy 5
- The FDA drug label specifies that previously existing thyroid disorders do not necessarily contraindicate lithium treatment, but careful monitoring during stabilization allows for correction of changing thyroid parameters 1
- Supplemental thyroid treatment may be used when hypothyroidism develops during lithium therapy, with the drug label recommending continued monitoring throughout treatment 1