Does physiologic stress and inflammation cause low T3 and high reverse T3 by altering deiodinases?

Nonthyroidal illness syndrome (NTIS), often referred to as "sick euthyroid syndrome," is a well-documented metabolic adaptation to systemic stress, such as sepsis, trauma, or severe inflammation. This condition is characterized by a specific laboratory profile: low circulating levels of active triiodothyronine (T3) and elevated levels of reverse T3 (rT3), while thyroid-stimulating hormone (TSH) often remains within the normal range or is slightly suppressed.

Mechanistic basis of deiodinase shifting

The transition to an NTIS pattern is driven by the coordinated regulation of deiodinase enzymes, which control the activation and inactivation of thyroid hormones:

• Increased Inactivation (D3): Inflammatory cytokines (such as IL-6 and TNF-alpha) and cortisol upregulate Type 3 deiodinase (D3). D3 is the primary inactivating enzyme; it shunts thyroxine (T4) into inactive rT3 and further degrades active T3 into diiodothyronine (T2). This upregulation is a hallmark of the acute phase response to illness.
• Reduced Activation (D1 and D2): Simultaneously, systemic inflammation suppresses the activity of Type 1 (D1) and Type 2 (D2) deiodinases. D1 and D2 are responsible for the "outer ring" deiodination that converts T4 into active T3. The reduction in these enzymes directly limits the production of the body’s most metabolically active thyroid hormone.
• Bioavailability: The resulting high rT3 levels can further interfere with thyroid function by potentially competing for transport proteins or inhibiting remaining deiodinase activity, compounding the low T3 state.

Clinical significance

Research across diverse patient populations, including those in intensive care and patients with severe COVID-19, shows that the degree of T3 suppression and rT3 elevation correlates strongly with the severity of the underlying illness and mortality risk. While this shift is considered an adaptive mechanism to conserve energy and prevent protein catabolism during acute crisis, persistent NTIS is associated with poorer clinical outcomes and delayed recovery.

Bottom line

The claim is strongly supported by clinical and mechanistic evidence. Physiologic stress and inflammation shift thyroid metabolism toward inactivation by increasing D3 activity and reducing D1/D2 activity, resulting in the characteristic low T3/high rT3 pattern of nonthyroidal illness.