Does inflammation reduce T4-to-T3 conversion by downregulating deiodinase activity?

Systemic inflammation is a primary driver of Non-Thyroidal Illness Syndrome (NTIS), where thyroid hormone metabolism is altered despite the absence of intrinsic thyroid disease. In this state, the body’s ability to generate active triiodothyronine (T3) from its precursor, thyroxine (T4), is significantly impaired.

Mechanistic pathways

The conversion of T4 to T3 occurs primarily in peripheral tissues through the actions of iodothyronine deiodinases, specifically Type 1 (D1) and Type 2 (D2).

• Cytokine-mediated suppression: Pro-inflammatory cytokines, particularly IL-6 and TNF-alpha, have been shown to directly downregulate the expression and catalytic activity of D1 and D2. In cell models and clinical studies, elevated IL-6 levels correlate with decreased hepatic D1 expression, which is responsible for a substantial portion of circulating T3.
• Oxidative stress: Deiodinases are selenoproteins that require a reduced environment to function. Inflammation-induced oxidative stress depletes glutathione and other antioxidant systems, impairing the deiodinase enzymes' ability to perform the outer-ring deiodination required to create T3.
• Induction of Type 3 Deiodinase (D3): While inflammation suppresses the "activating" enzymes (D1/D2), it simultaneously upregulates Type 3 deiodinase (D3). D3 is an "inactivating" enzyme that converts T4 into reverse T3 (rT3) and T3 into T2, further depleting the pool of active hormone.

Clinical evidence

The link between systemic inflammation and reduced T3 is well-documented across various disease states:

• Critical illness and sepsis: In patients with sepsis, "low T3 syndrome" (FT3 <3.1 pmol/L) is a hallmark of disease severity. Studies show that the degree of T3 suppression is proportional to the level of inflammatory markers like C-reactive protein (CRP).
• Chronic inflammatory conditions: In patients with chronic conditions such as ankylosing spondylitis or COPD, active inflammation is an independent predictor of lower free T3 (FT3) levels.
• Metabolic inflammation: In metabolic dysfunction-associated steatohepatitis (MASH), liver inflammation has been directly linked to reduced hepatic DIO1 (D1) expression and lower systemic T3 availability.

Bottom line

Inflammation reduces circulating T3 levels by downregulating the D1 and D2 deiodinase enzymes while simultaneously increasing D3-mediated inactivation. This metabolic shift is a core feature of non-thyroidal illness syndrome and correlates with the severity of the inflammatory state.