The aim of this multidisciplinary study is to explore the possibility to treat NonThyroidal Illness Syndrome (NTIS), affecting the majority of patients hospitalized in the Intensive Care Units (ICU)s. NTIS is considered an adaptative response to reduced calories availability and, therefore, treatment is currently not recommended. The interventional clinical trials, performed so far, failed to demonstrate any benefit of treatment with thyroid hormones.
Recently, we analyzed epidemiological, clinical and laboratory characteristics of patients that presented NTIS during the first wave of COVID-19 pandemic, demonstrating that this syndrome is associated with the markers of disease severity. We analyzed also the effects of NTIS on water and electrolyte balance at the periphery during the second wave of COVID-19 pandemic (manuscript in preparation), demonstrating that it is associated with water and salt retention, in a picture that resembles that observed in severe hypothyroid patients with myxedema. We, therefore, hypothesize that NTIS is, indeed, manifestation of an acute form of hypothyroidism and needs to be treated. This study is also aimed to better understand the underlying mechanism of NTIS and its correlation with the psychological conditions at the basis of acute stress accumulation, bringing new insights into the pathogenesis of the severity of this syndrome
The three aims are:
Aim 1 Validate the utility of measurement of fluid and electrolyte balance at the periphery, by Bioelectrical Impedance Analysis (BIA) in patients with NTIS hospitalized in ICUs
Aim 2 Evaluate the efficacy of treatment with T3 in these patients in an interventional clinical trial based on the endpoints validated in the first aim.
Aim 3 Investigate if the development of NTIS is associated with exposure to psychological chronic stress, and with the presence of psychopathological symptoms, by means of a psychometric assessment.
The innovation of the projects relies in the identification of new markers of the T3 action at the periphery. These markers of T3 action can be used as better endpoints in a new interventional clinical trial aimed to evaluate the benefit of T3 treatment in patients with critical illness that show the occurrence of NTIS while they are hospitalized in ICUs. We postulate that the reason why many different clinical trials, performed in patients with NTIS, failed to demonstrate benefit of T3 treatment, relies in the choice of inappropriate endpoints. Our preliminary results indicate that NTIS should be considered as an acute form of severe hypothyroidism, responsible for the occurrence of an anasarcatic condition, similar to that observed in myxedematous hypothyroidisms and, therefore, requiring an appropriate treatment. In addition, we demonstrated that the pathogenesis of NTIS could be explained by a direct effect of T3 on the Na+/K+ pump. Based on these observations, we postulated that the water and salt retention, as easily measured by BIA, could represent a possible optimal endpoint for a new clinical interventional study, based on the administration of T3.
Neither the impact of early life stress, which is presumed to induce developmental programming changes in HPT and HPA functioning, nor the impact of adult stress on susceptibility to NIST in critically ill patients has ever been studied. Innovatively, this project will investigate this specific topic. Moreover, this research study will assess, for the first time, if psychological alterations emerge in NTIS patients during the health recovery months. In case this last aspect will be confirmed, future efforts should be implemented for developing interventional psychotherapeutic and pharmacological protocols to counteract such symptomatology.
Aim 1 Expected results
We expect to observe the same correlation that we found in COVID-19 patients between FT3 serum values and hydration as well as the Nae:Ke ratio, thus validating the use of these BIA parameters as endpoints for the clinical interventional trials with T3 in the Aim 2. In addition, we expect to see the same correlation between the mRNA expression levels of the two genes that code for the two major isoforms of the Na+/K+ pump and the serum levels of FT3, to confirm that these two genes are targets of T3 action at the periphery and are involved in the development of the edema and an anasarcatic condition observed in critically ill patients with NTIS.
Aim 2 Expected results
We expect to demonstrate whether treatment with T3 would be beneficial to patients hospitalized in ICUs that show the occurrence of NTIS. In other words, we expect to answer the question whether these patients should be treated or not.
Aim 3 Expected results
Considering the stress-induced priming hypothesis, we expect that NITS is a phenomenon particularly present in subjects with a history of chronic stress exposure. Moreover, we expect that such medical condition is associated with the development of psychopathological symptoms after discharge from ICU. Symptoms that we expect to be attenuated in the experimental group pharmacologically treated with T3.