Mechanism of Lithium-Induced Hypothyroidism
Direct Mechanism of Action
Lithium causes hypothyroidism primarily by inhibiting thyroid hormone synthesis and release at multiple points in the hypothalamic-pituitary-thyroid axis, leading to elevated TSH levels and subsequent thyroid dysfunction. 1, 2
The specific mechanisms include:
Inhibition of thyroid hormone release: Lithium directly blocks the release of T3 and T4 from the thyroid gland, even when synthesis is normal 1, 2
Interference with iodine uptake: Lithium can elevate Iodine-131 uptake in the thyroid gland, disrupting normal thyroid hormone production pathways 1
TSH elevation without compensatory hormone increase: During lithium therapy, both basal and TRH-stimulated TSH values become significantly elevated compared to pre-treatment levels, yet T3, T4, FT3, and FT4 levels often remain within normal range initially, indicating subclinical hypothyroidism 2
Development of compensatory goiter: The sustained TSH elevation can lead to euthyroid goiter formation as the thyroid attempts to compensate for impaired hormone release 1, 2
Temporal Pattern and Clinical Significance
Subclinical hypothyroidism develops early: Significant increases in basal TSH above the normal range occur in approximately 83% of patients (10 out of 12) during lithium therapy, with TRH-stimulated TSH rising in 92% of patients (11 out of 12) 2
Median time to thyroid dysfunction: The median duration between lithium initiation and the first abnormal thyroid test result is approximately 341 days (roughly 11 months) 3
Transitory nature in some cases: The impairment of the hypothalamic-pituitary-thyroid axis is transitory in the majority of cases, though some patients develop persistent hypothyroidism requiring thyroid hormone replacement 2
Risk Factors and Prevalence
Female predominance: Women show significantly greater susceptibility to lithium-induced thyroid dysfunction, with approximately 22% of female patients developing features of hypothyroidism compared to no abnormalities in male patients in long-term studies 4
Overall prevalence: The four-year cumulative risk of hypothyroidism with lithium is 8.8%, which is 1.39-fold higher than the lowest-risk mood stabilizer (oxcarbazepine at 6.3%) 5
Autoimmune component: A significant proportion of lithium-treated patients develop abnormally high levels of anti-TPO and anti-TG antibodies, which correlate with TSH and fT3 concentrations, suggesting lithium may trigger or unmask autoimmune thyroid processes 4
Critical Clinical Implications
Subclinical hypothyroidism is underdiagnosed: Cross-sectional studies significantly underestimate the true prevalence of subclinical hypothyroidism during lithium therapy; longitudinal monitoring reveals much higher rates 2
Duration of therapy: Interestingly, there is no significant association between duration of lithium administration beyond 10 years and worsening thyroid dysfunction, suggesting the effect plateaus rather than progressively worsens 4
Thyroid hormone replacement is advisable: Thyroxine replacement in lithium-treated patients should be considered even for subclinical hypothyroidism to prevent progression and the risk of subsequent goiter development 2
Monitoring Requirements
Baseline assessment: Complete blood count, thyroid function tests (TSH, T3, T4), urinalysis, BUN, creatinine, and serum calcium should be obtained before lithium initiation 6
Ongoing surveillance: Lithium levels, renal function, and thyroid function should be monitored every 3-6 months throughout treatment 6, 7
Testing frequency disparity: Patients taking lithium are tested for hypothyroidism 2.26-3.05 times more frequently than those on other mood stabilizers, which may partially explain the higher reported rates 5