Low triiodothyronine in metabolic and inflammatory stress: A context-dependent model of thyroid adaptation

Background. Low triiodothyronine status has been described in a wide range of physiological and pathological conditions, including energy restriction, critical illness, and systemic inflammation. In the literature, these alterations are commonly referred to as the low T₃ state. Traditionally, they have been interpreted within the framework of the Non-Thyroidal Illness Syndrome (NTIS). However, accumulating experimental and clinical evidence suggests that a similar biochemical phenotype may arise in different systemic contexts through distinct regulatory mechanisms. Thus, low triiodothyronine status may be considered a context-dependent phenotype of systemic adaptation that develops under diverse metabolic and immune conditions. Aim. To summarize current pathophysiological concepts of low triiodothyronine status in systemic inflammatory and metabolic stress, to analyze their limitations, and to propose an integrative context-dependent model of thyroid adaptation. Materials and Methods. The study is a literature review. A bibliographic analysis of scientific literature published between 2015 and 2025 was conducted using the PubMed, Scopus, ScienceDirect, Google Scholar, and MEDLINE databases. The following keywords were used: adaptive physiological processes, deiodinases, thyroid hormones, energy metabolism, cytokines, and allostatic load. Clinical, experimental, and review studies meeting contemporary evidence-based medicine standards were included in the analysis. The study was conducted as a private initiative of the authors, without grant support and state registration of the topic. Research Ethics. This review was conducted using previously published studies performed in accordance with current bioethical standards. Results. Analysis of the literature indicates that most current concepts interpret low T₃ either as an energy-saving adaptive response or as a marker of disease severity. At the same time, the role of the immune system as an active regulatory component of thyroid homeostasis remains insufficiently addressed. The present review proposes a context-dependent model of thyroid adaptation, according to which an identical biochemical phenotype of low T₃ may develop under different systemic conditions – energy deficit or systemic inflammation – through distinct regulatory mechanisms. Particular attention is given to the integration of neuroendocrine, metabolic, and immune signals, including the roles of cytokines, deiodinases, and the potential involvement of iodine-dependent mechanisms of innate immunity. A central element of the proposed model may be the functional interaction between the thyroid axis and phagocytic activity. Conclusions. Low triiodothyronine status should be considered a context-dependent phenotype of systemic adaptation that emerges from interactions between metabolic, immune, and neuroendocrine regulatory processes. The proposed model expands current understanding of the mechanisms underlying low T₃ and provides a conceptual framework for future mechanistic and clinical studies. Keywords: endocrinology, literature review, deiodinases, thyroid hormones, energy metabolism, cytokines.