Low T3 syndrome as a predictor of poor prognosis in peripheral T-cell lymphomas

Purpose The purpose of the study was to evaluate the prognostic value of low T3 syndrome in peripheral T-cell lymphomas (PTCLs). Methods One hundred and seventy-four patients of newly diagnosed PTCLs were enrolled in the study. We performed statistical analysis based on the clinical data collected. Results Thirty-Six (20.69%) patients had low T3 syndrome at first admission. Results suggested that the patients with higher score of ECOG PS, International Prognostic Index (IPI) and Prognostic Index for T-cell lymphoma (PIT), bone marrow involvement and lower level of albumin tended to develop low T3 syndrome. The median progression-free survival (PFS) and overall survival (OS) were 10 months and 36 months, respectively, for all patients. Pre-existing low T3 syndrome was in correlation with worse PFS and OS. Patients with low T3 syndrome showed worse PFS (4 months vs 13 months, P = 0.0001) and OS (7 months vs 83 months, P < 0.0001) than patients without low T3 syndrome. IPI and PIT, respectively, combined with low T3 syndrome improved the ability to predict OS and PFS of PTCLs. Conclusions The study indicated that low T3 syndrome may be a good candidate for predicting prognosis of peripheral T-cell lymphomas (AU)

The prevalence of thyroid disorders in COVID-19 patients: a systematic review and meta-analysis.

OBJECTIVES: To conduct a systematic review and meta-analysis to evaluate the prevalence of thyroid disorders in COVID-19 patients. DATA SOURCES: Scopus, PubMed, ISI Web of Science, and Google Scholar databases were used in this review. We also consider the results of grey literature. STUDY SELECTIONS: Cohort, cross-sectional, and case-control studies were included. DATA EXTRACTION AND SYNTHESIS: The required data were extracted by the first author of the article and reviewed by the second author. The Pooled prevalence of outcomes of interest was applied using the meta-prop method with a pooled estimate after Freeman-Tukey Double Arcsine Transformation to stabilize the variances. OUTCOMES AND MEASURED: The different thyroid disorders were the main outcomes of this study. The diseases include non-thyroidal illness syndrome, thyrotoxicosis, hypothyroidism, isolated elevated free T4, and isolated low free T4. RESULTS: Eight articles were included in our meta-analysis(Total participants: 1654). The pooled prevalence of events hypothyroidism, isolated elevated FT4, isolated low FT4, NTIS, and thyrotoxicosis were estimated (Pooled P = 3%, 95% CI:2-5%, I2: 78%), (Pooled P = 2%, 95% CI: 0-4%, I2: 66%), (Pooled P = 1%, 95% CI: 0-1%, I2: 0%), (Pooled P = 26%, 95% CI: 10-42%, I2: 98%), and (Pooled P = 10%, 95% CI: 4-16%, I2: 89%), respectively. CONCLUSION: Thyroid dysfunction is common in COVID-19 patients, with a high prevalence of non-thyroidal illness syndrome (NTIS) and thyrotoxicosis. Our meta-analysis found a 26% prevalence of NTIS and a 10% prevalence of thyrotoxicosis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022312601.

Evaluation of non-thyroidal illness syndrome in shock patients admitted to pediatric intensive care unit in a developing country.

During critical illness, children my experience various changes in their thyroid hormone levels. Such changes are termed non-thyroidal illness syndrome (NTI). The extent of change correlates with the severity of the illness and its outcomes in critically ill patients. This study aimed to investigate the correlation between the severity of shock and thyroid hormone derangement. This prospective observational study included forty patients aged one month to five years who were admitted to the pediatric intensive care unit (PICU) with shock. Thyroid function tests were conducted on admission, after shock reversal, and five days later. NTI patterns were observed in 70% of patients. The PIM2 score showed a significant negative correlation with T3 (r = - 0.353, p = 0.026) and FT3 levels on admission (r = - 0.417, p = 0.007). Furthermore, after shock reversal, the PIM2 score continued to exhibit significant negative correlations with T4 (r = - 0.444, p = 0.004), T3 (r = - 0.329, p = 0.038), FT3 (r = - 0.355, p = 0.025), and FT4 levels (r = - 0.379, p = 0.016).    Conclusion: This study underscores the high prevalence of NTI in PICU shock patients and suggests monitoring thyroid hormone levels for outcome prediction and treatment guidance. Further research is needed to optimize NTI management in critically ill children. What is Known: • Non-thyroidal illness syndrome (NTIS) is a condition observed in critically ill patients. • There has been limited research on NTI in children, and existing studies have generated conflicting results regarding the relationship between thyroid hormones and clinical outcomes in cases of sepsis and septic shock. What is New: • The study has revealed dynamic changes in free triiodothyronine (FT3) levels during the process of shock reversal and recovery in children who experienced shock. • A significant negative correlation was found between the Pediatric Index of Mortality 2 (PIM2) score and several thyroid hormone levels, including FT3 on admission and T4, FT3, and FT4 on shock reversal.

Low T3 syndrome as a predictor of poor prognosis in peripheral T-cell lymphomas.

PURPOSE: The purpose of the study was to evaluate the prognostic value of low T3 syndrome in peripheral T-cell lymphomas (PTCLs). METHODS: One hundred and seventy-four patients of newly diagnosed PTCLs were enrolled in the study. We performed statistical analysis based on the clinical data collected. RESULTS: Thirty-Six (20.69%) patients had low T3 syndrome at first admission. Results suggested that the patients with higher score of ECOG PS, International Prognostic Index (IPI) and Prognostic Index for T-cell lymphoma (PIT), bone marrow involvement and lower level of albumin tended to develop low T3 syndrome. The median progression-free survival (PFS) and overall survival (OS) were 10 months and 36 months, respectively, for all patients. Pre-existing low T3 syndrome was in correlation with worse PFS and OS. Patients with low T3 syndrome showed worse PFS (4 months vs 13 months, P = 0.0001) and OS (7 months vs 83 months, P < 0.0001) than patients without low T3 syndrome. IPI and PIT, respectively, combined with low T3 syndrome improved the ability to predict OS and PFS of PTCLs. CONCLUSIONS: The study indicated that low T3 syndrome may be a good candidate for predicting prognosis of peripheral T-cell lymphomas.

The prevalence, hospitalization outcomes and risk factors of euthyroid sick syndrome in patients with diabetic ketosis/ketoacidosis.

BACKGROUND: To investigate the prevalence of euthyroid sick syndrome (ESS) and to evaluate the outcomes and risk factors associated with ESS among hospitalized patients with diabetic ketosis (DK) or diabetic ketoacidosis (DKA). METHODS: Laboratory and clinical data of 396 adult hospitalized DK/DKA patients with or without ESS were collected and analyzed. Spearman linear analysis and multivariable logistic regression analyses were used to evaluate correlated factors of thyroid hormones and risk factors of ESS. RESULTS: Most of the individuals were diagnosed with type 2 diabetes (359/396, 90.7%). The prevalence of ESS was 57.8% (229/396). Patients in ESS group were older and had a longer course of diabetes. Levels of thyroid hormones, serum lipids, and parameters reflecting acidosis were significantly decreased in ESS group. The proportion of patients with infection, acute renal injury and DKA was significantly higher in ESS group than in control group, accompanied by longer hospitalization stay and higher hospitalization costs. Free triiodothyronine positively correlates with albumin, eGFR, parameters reflecting acidosis and lipid profiles (All P < 0.001), and negatively correlates with age, onset age, 24-h urine albumin, hsCRP and WBC count (All P < 0.001). Hypoalbuminemia, low level of carbon dioxide combining power, high level of HbA1c and WBC, and co-infection are shown to be risk factors for ESS (OR = 0.866, 0.933, 1.112, 1.146, 1.929, respectively; All P < 0.05). CONCLUSIONS: The prevalence of ESS was high in adult DK/DKA patients. Patients with ESS had inferior clinical and socioeconomic outcomes. Early recognition and management of patients with ESS may be necessary to improve outcome.

Low T3 syndrome predicts more adverse events in patients with hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common cardiac genetic disorder that clinically manifests with sudden death and progressive heart failure. Moreover, thyroid dysfunction is associated with increased cardiovascular morbidity and mortality risks. Therefore, this study aimed to clarify whether thyroid hormones could serve as an independent predictor of adverse events in patients with HCM. METHODS: The cohort consisted of 782 patients with HCM who had thyroid hormones baseline data and were admitted to the Affiliated Hospital of Jiaxing University. Patients were divided into two groups according to serum levels of free triiodothyronine (fT3): the normal fT3 and low triiodothyronine (T3) syndrome groups. Low T3 syndrome was defined as fT3 < 2.43 pmol/L with a normal thyroid-stimulating hormone (TSH) level. Patients whose TSH levels were abnormally high or abnormally low were excluded from this study. The primary endpoint was the occurrence of sudden cardiac death (SCD) events, and the secondary endpoint was a composite of worsening heart failure (WHF) events, including heart failure death, cardiac decompensation, hospitalization for heart failure, and HCM-related stroke. The Kaplan-Meier and Cox regression were performed for the survival analysis. RESULTS: After a median follow-up of 52 months, 75 SCD events and 134 WHF events were recorded. The Kaplan-Meier survival curves showed that the cumulative incidence of SCD events and WHF events were significantly higher in patients with low T3 syndrome (log-rank p = .02 and log-rank p = .001, respectively). Furthermore, multivariate Cox regression analysis demonstrated that low T3 syndrome is a strong predictor of SCD events and WHF events (adjusted hazard ratio [HR: 1.53, 95% confidence interval [CI]: 1.13-2.24, p < .01; HR: 3.87, 95% CI: 2.91-4.98, p < .001, respectively). CONCLUSIONS: Low T3 syndrome is highly prevalent among patients with HCM and was independently associated with an increased risk of SCD events and WHF events. The routine assessment of serum fT3 levels may provide risk stratification in this population.

Critically ill patients: Histopathological evidence of thyroid dysfunction.

PURPOSE: Critical illness is characterized by severe biphasic physical and metabolic stress as result of systemic inflammatory response syndrome and/or multiple organ dysfunction syndrome, and is frequently associated with non-thyroidal illness. Purpose of this study is to better understand the cytomorphological basis of NTI by performing histopathological examinations of thyroid gland on autopsies of patients who died from critical illness. METHODS: Histopathological examination of thyroid gland of 58 critically ill patients was performed in our hospital. The cases included 24 cases of burn injury, 24 cases of traumatic brain injury, and 10 cases of cerebral stroke. Thyroid samples obtained during autopsy were preserved in formol saline and stained with hematoxylin and eosin. The sections were visualized under light microscopy. RESULTS: Out of 58 cases examined, 21 patients showed normal thyroid findings, and rest of the cases had unusual thyroid findings in the histopathological study. The principal finding was distortion of thyroid follicular architecture. Other findings include mononuclear cell infiltration, clumping of thyroglobulin, and exhaustion of thyroid follicles. CONCLUSION: Critical illness produces metabolically damaging effects on thyroid gland, which functionally corresponds to a state of low T3 syndrome. These changes are more pronounced in BI and cerebral stroke than in TBI.

The severity of valvular heart disease in euthyroid individuals is associated with thyroid hormone levels but not with TSH levels.

Background: Abnormal thyroid function is a metabolic disorder and can lead to several complications, including cardiovascular diseases. In this study, we aimed to examine the relationship between clinical traits and outcomes and the thyroid hormone level of euthyroid individuals with valvular heart disease (VHD). Method: The thyroid function was evaluated in 526 euthyroid VHD patients and 155 healthy control people. As well as clinical indicators were collected and analyzed. Results: No difference in TSH levels (p>0.05) was recorded; however, fT3, TT3, and TT4 levels were lower in the euthyroid VHD patients than in healthy control(4.3 vs 4.63; 1.37 vs 1.48; 97.7 vs 102.09, respectively, all p<0.05), while the fT4 level was higher (12.91 vs 12.35, p<0.05). Moreover, all showed a continuous trend with the change of NYHA grade which does not consist of the incidence of euthyroid sick syndrome(ESS). Further analysis showed that for every 10-fold increase in BNP, fT4 increases by 83%, fT3 decreases by 30%, and TT3 decreases by 12% after being adjusted for other influencing factors. Meanwhile, adjusted fT4 was correlated with multiple worse clinical indicators, which were influenced by age. Conclusion: Thyroid hormones are widely regulated in VHD patients even with acceptable cardiac function, except for TSH level. And the adjusted fT4 is related to worse clinical indicators and outcomes which are only recorded in patients under 53 years old.

Low T3 syndrome is associated with 30-day mortality in adult patients with fulminant myocarditis.

Background: Fulminant myocarditis (FM) is a critical disease with high early mortality. Low triiodothyronine syndrome (LT3S) was a strong predictor of poor prognosis of critical diseases. This study investigated whether LT3S was associated with 30-day mortality in FM patients. Methods: Ninety-six FM patients were divided into LT3S (n=39, 40%) and normal free triiodothyronine (FT3) (n=57, 60%) groups based on serum FT3 level. Univariable and multivariable logistic regression analyses were performed to identify independent predictors of 30-day mortality. Kaplan-Meier curve was used to compare 30-day mortality between two groups. Receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were used to assess the value of FT3 level for 30-day mortality prediction. Results: Compared to normal FT3 group, LT3S group had higher incidence of ventricular arrhythmias, worse hemodynamics, worse cardiac function, more severe kidney impairment, and higher 30-day mortality (48.7% vs. 12.3%, P<0.001). In univariable analysis, LT3S (odds ratio [OR]:6.786, 95% confidence interval [CI]:2.472-18.629, P<0.001) and serum FT3 (OR:0.272, 95%CI:0.139-0.532, P<0.001) were significant strong predictors of 30-day mortality. After adjustment for confounders in multivariable analysis, LT3S (OR:3.409, 95%CI:1.019-11.413, P=0.047) and serum FT3 (OR:0.408, 95%CI:0.199-0.837, P=0.014) remained independent 30-day mortality predictors. The area under the ROC curve of FT3 level was 0.774 (cut-off: 3.58, sensitivity: 88.46%, specificity: 62.86%). In DCA, FT3 level showed good clinical-application value for 30-day mortality prediction. Conclusion: In FM patients, LT3S could independently predict 30-day mortality. FT3 level was a strong 30-day mortality predictor and a potentially useful risk-stratification biomarker.

[The impact of low T3 syndrome on the prognosis of patients with newly diagnosed multiple myeloma].

Objective: This study aimed to examine the relationship between low T3 syndrome (LT3S) and the prognosis of newly diagnosed multiple myeloma (NDMM) patients. Methods: A retrospective examination of 211 NDMM patients treated at the Department of Hematology, Jiangsu Provincial People's Hospital from July 2009 to December 2020 was performed, and all patients received thyroid function testing to determine if they had LT3S. We investigated the relationship between LT3S and clinical features, as well as its impact on MM prognosis. Results: Of the 211 patients, 119 were males, and 92 were females, with a median age of 60 (33-86) years. Patients with LT3S had significantly higher levels of ß(2)-microglobulin, C-reactive protein, and blood creatinine compared to those with normal T3 levels. They also had lower levels of hemoglobin, platelets, and serum albumin, as well as more advanced ISS stages (P<0.001) . Patients with LT3S had shorter progression-free survival (PFS) (16 months vs 30 months, P=0.003) and overall survival (OS) (57 months vs 75 months, P=0.004) than patients without LT3S. LT3S was found to be a standalone unfavorable factor in multivariate analysis, LT3S was an independent unfavorable factor in predicting both PFS (HR=2.114, 95% CI 1.271-3.516, P=0.004) and OS (HR=2.231, 95% CI 1.088-4.577, P=0.029) . Conclusions: Low T3 syndrome was an independent unfavorable prognostic predictor for NDMM.

Thyroid Function in Newly Diagnosed HIV-positive Patients.

BACKGROUND: As of 2019, the highest prevalence of human immunodeficiency virus (HIV) in India is seen in the Northeastern states. Endocrine and metabolic disturbances can occur in HIV infection. Thyroid dysfunction is one of the common endocrinopathies. In HIV infection, thyroid function abnormalities are seen in about 4-35% of adult patients. Thyroid function abnormalities range from overt hypothyroidism, subclinical hypothyroidism, and sick euthyroid syndrome to overt hyperthyroidism. Among them, subclinical hypothyroidism is the commonest abnormality. To our knowledge, there have been no studies from Northeastern India done in this regard. AIMS AND OBJECTIVES: To study the thyroid function in newly diagnosed cases of HIV infection attending anti-retroviral therapy (ART) center, Assam Medical College. To estimate the prevalence and types of thyroid dysfunction in newly diagnosed HIV-infected individuals. To study thyroid dysfunctions with respect to age, sex, and cluster of differentiation (CD) 4 count. MATERIALS AND METHODS: Hospital-based observational study was done at a tertiary care centre of upper Assam on newly diagnosed HIV-positive patients who were not started on antiretroviral therapy and who attended the ART centre, Assam Medical College during the period of our study. History, examinations and laboratory investigations, including thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), and CD4 count, are done in all such patients, and only those who fulfilled the inclusion and exclusion criteria of our study are taken as study participants, and their findings tabulated. RESULTS AND OBSERVATIONS: A total of 95 newly diagnosed HIV-positive patients fulfilling the inclusion and exclusion criteria of our study were taken. In our study, a total of 36.84% of the patients had thyroid dysfunction. We got subclinical hypothyroidism, overt hypothyroidism, sick euthyroid syndrome, and overt hyperthyroidism as the types of thyroid dysfunction. Among all the types of thyroid dysfunction, subclinical hypothyroidism was the commonest abnormality in our study. Under sick euthyroid syndrome, we got only low FT3 as the biochemical abnormality. Thyroid dysfunctions were more common in females (42.3%) than males (35.8%) and were more common in the age group of 30-39 years. In the present study, among patients with thyroid dysfunction, it was seen that 51.43% of the patients had a CD4 cell count in the range 101-200 cells/mm3, whereas only 11.43% of patients had a CD4 cell count in the range <50 cells/mm3 and no patient had a CD4 cell count >500 cells/mm3 . CONCLUSION: In our study, we found that thyroid dysfunctions were common in newly diagnosed HIV-positive patients, the prevalence of which was much higher in the general population. Thyroid dysfunction was present in all the stages of the HIV disease.

Non-thyroidal Illness Syndrome (NTIS) is no independent predictor for mortality in ICU patients.

BACKGROUND: Low T3-(/T4-) syndrome, also known as non-thyroidal Illness Syndrome (NTIS) describes a decrease in free serum thyroid hormones without a concomitant increase in TSH, frequently observed in critically ill patients. However, whether NTIS is only a metabolic adaption to stress in critically ill or plays a crucial role as an independent risk factor for ICU mortality, remains unknown. Our study aimed to evaluate NTIS as an independent risk factor for increased ICU mortality. METHODS: All patients admitted to the interdisciplinary intensive care unit (ICU) at the University Hospital of Leipzig between 2008 and 2014 were retrospectively analyzed for thyroidal function. Baseline data, information on additional thyroid function tests, disease progression, hospital and ICU length of stay (LOS) and patient outcome were retrospectively analyzed from the hospitals digital information system. For statistical evaluation, univariate analysis, matched pairs analysis and multivariate logistic regression were conducted. RESULTS: One thousand, seven hundred ninety patients were enrolled in the study, of which 665 showed NTIS. Univariate analysis revealed a positive association of NTIS with ICU- and hospital-LOS, need for mechanical ventilation, incidence of sepsis, acute respiratory distress syndrome, acute liver failure and increased ICU mortality. Results of matched pair analysis confirmed these findings. In multivariate logistic regression, NTIS was associated with an increased ICU-LOS, increased duration of mechanical ventilation, acute kidney injury and liver failure, but showed no independent association with increased ICU-mortality. CONCLUSION: Duration of mechanical ventilation as well as incidence of acute kidney injury, sepsis and acute liver failure were detected as independent predictors of mortality in patients with NTIS. NTIS itself was no independent predictor of increased ICU-mortality.

Analysis of clinical features and 7-year all-cause mortality in older male patients with non-thyroidal illness syndrome on general wards.

PURPOSE: Older patients with non-thyroidal illness syndrome (NTIS) have a poor prognosis. However, there are few studies on the association of NTIS and mortality among older inpatients on general wards. In a 7-year retrospective observational study, we aimed to investigate the clinical features of NTIS and the association of NTIS and all-cause mortality in older inpatients. METHODS: A total of 959 older male inpatients whose average age was 86.3 ± 8.1 years were enrolled and divided into the NTIS group and non-NTIS group. Cox models were performed to explore the association of thyroid hormone level and mortality. RESULTS: Patients had more respiratory disease and chronic kidney disease in the NTIS than in the non-NTIS group, especially in primary nursing care, respiratory failure and haemodialysis patients; serum total protein, albumin, prealbumin, haemoglobin, uric acid and high-density lipoprotein cholesterol levels were lower, and urea nitrogen and fasting blood glucose levels were higher, in the NTIS than in the non-NTIS group. Patients in the NTIS group had a lower survival rate over 7 years follow-up (P < 0.01). A lower free T3 level was associated with all-cause mortality with a HR of 1.50 (1.36, 1.66). Lower free T4 level was associated with reduced all-cause mortality with a HR of 0.91 (0.88, 0.94) even after adjusting for confounding factors (P < 0.01). CONCLUSIONS: Among older male inpatients, the survival rate was lower in the NTIS group. A reduced free T3 level with low albumin and Hb levels was associated with all-cause mortality; moreover, a higher free T4 in the normal range may be a strong predictor for long-term mortality risk in hospitalised older male patients.

Non-thyroidal illness syndrome in chronic diseases: role of irisin as modulator of antioxidants.

OBJECTIVE: Non-thyroidal-illness syndrome (NTIS) refers to condition found in chronic diseases that is an adaptive mechanism. However, oxidative stress is related to NTIS in a vicious circle, due to deiodinases alteration and negative effects of low T3 on antioxidant levels or activity. Muscle is one of the main targets of thyroid hormones and it can secrete a myokine named irisin, which is able to induce the browning of white adipose tissue, energy expenditure and protect against insulin resistance. Inconclusive data have been reported about irisin role in chronic diseases. Moreover, no correlation with antioxidants has been investigated. Therefore, we performed a case-control study with the primary endpoint to evaluate irisin levels in two models of NTIS, such as chronic heart failure (CHF) and chronic kidney disease (CKD) during haemodialytic treatment. The secondary endpoint was the correlation with total antioxidant capacity (TAC) to establish a possible role of irisin in the modulation of antioxidant systems. PATIENTS AND METHODS: Three groups of subjects were enrolled. Group A included CHF patients (n=18; aged 70.22 ± 2.78 ys; BMI ± 27.75 ± 1.28 kg/m2); Group B included CKD patients (n=29; aged 67.03 ± 2.64; BMI 24.53 ± 1.01); finally, 11 normal subjects (Group C) have been enrolled as controls. Irisin has been evaluated by ELISA method and Total Antioxidant Capacity (TAC) by spectrophotometric method. RESULTS: Irisin was significantly higher in Group B vs. A and C groups (Mean ± SEM: 20.18 ± 0.61 ng/ml vs. 2.77 ± 0.77 and 13.06 ± 0.56, respectively; p<0.05); a significant correlation between irisin and TAC was observed in group B. CONCLUSIONS: These preliminary data suggest a possible role of irisin in the modulation of antioxidants in two chronic syndromes with low T3 (i.e., CHF and CKD) with differential pattern in these two models studied. Further insights are needed to confirm this pilot study, which could be the basis for a longitudinal investigation, to assess a prognostic role of irisin with possible therapeutic implications.

Low T3 syndrome as a predictor of poor outcomes in patients with follicular lymphoma.

The aim of this study was to investigate the prognostic value of low T3 syndrome in follicular lymphoma (FL). A total of 221 FL patients with detailed serum thyroid hormone levels and other complete clinical data were enrolled. Baseline features associated with low T3 syndrome were analyzed and balanced by propensity score matching. Univariate and multivariate regression analyses were performed to determine independent risk factors for progression-free survival (PFS) and overall survival (OS). A receiver operating characteristic (ROC) curve was plotted, and the area under the curve (AUC) was calculated to assess the predictive accuracy of FL international prognostic index FLIPI-1/FLIPI-2 and low T3 syndrome. A total of 22 patients (10.0%) had low T3 syndrome at diagnosis, which was associated with poor PFS and OS in the rituximab era. It is an independent prognostic factor for PFS and OS. Low T3 syndrome and FLIPI-1/FLIPI-2 significantly increased the AUC of PFS and OS compared to FLIPI-1/FLIPI-2 alone. Low T3 is a risk factor for POD24. In conclusion, low T3 syndrome may be a good candidate for predicting the prognosis of CLL in future clinical practice. Our study demonstrates that low T3 syndrome is associated with poorer survival outcomes in FL patients.

Evolution of non-thyroidal illness syndrome in acute decompensation of liver cirrhosis and acute-on-chronic liver failure.

Background and aims: Non-thyroidal illness syndrome (NTIS) is frequent in critically ill patients and associated with adverse outcomes. We aimed to characterize the evolution of NTIS in patients with acute decompensation (AD) of cirrhosis and acute-on-chronic liver failure (ACLF), since NTIS is not well described in these newly defined syndromes. Methods: Thyroid hormones (TH) were quantified at baseline in consecutive patients with cirrhosis. In addition, 76 inflammatory mediators were quantified by proximity extension analysis assay in a subgroup of patients. Associations between TH, cirrhosis stage, mortality and inflammation were assessed. Results: Overall, 437 patients were included, of whom 165 (37.8%), 211 (48.3%), and 61 (14%) had compensated cirrhosis (CC), AD, and ACLF. FT3 concentrations were lower in AD versus CC, and further decreased in ACLF. Importantly, NTIS was present in 83 (39.3%) patients with AD and in 44 (72.1%) patients with ACLF (P<0.001). Yet, TSH and TSH-based indexes (TSH/FT3-ratio, thyroid index) showed an U-shaped evolution during progression of cirrhosis, suggesting a partially preserved responsiveness of the hypothalamus and pituitary in AD. Infections were associated with lower FT3 concentrations in AD, but not in ACLF. Low FT3 concentrations correlated significantly with 90-day mortality. Both, AD/ACLF and NTIS, were associated with signatures of inflammatory mediators, which were partially non-overlapping. Conclusion: NTIS is frequent already in AD and therefore precedes critically illness in a subgroup of patients with decompensated cirrhosis. This might constitute a new paradigm of TH signaling in cirrhosis, offering opportunities to explore preventive effects of TH in AD.

Euthyroid sick syndrome and its association with complications of type 1 diabetes mellitus onset.

OBJECTIVE: To evaluate (i) the prevalence and association of euthyroid sick syndrome (ESS) [decreased FT3 and/or FT4 and normal/decreased TSH] with severity indexes of type 1 diabetes mellitus (T1DM) onset such as diabetic ketoacidosis (DKA) and kidney damage [acute kidney injury (AKI) based on KDIGO criteria, acute tubular necrosis (ATN), renal tubular damage (RTD)], (ii) relationship between clinical/metabolic parameters at T1DM onset and thyroid hormones, and (iii) ESS as a prognostic indicator of delayed recovery from kidney damage. METHODS: A total of 161 children with T1DM onset were included. RTD was defined by abnormal urinary beta-2-microglobulin and/or neutrophil gelatinase-associated lipocalin (NGAL) and/or tubular reabsorption of phosphate <85% and/or fractional excretion of Na>2%. ATN was defined by RTD+AKI. RESULTS: Of 161 participants, 60 (37.3%) presented ESS. It was more prevalent in case of more severe T1DM presentation both in terms of metabolic derangement (DKA) and kidney function impairment (AKI, RTD and ATN). Only ATN, however, was associated with ESS at adjusted analysis. FT3 inversely correlated with serum triglycerides and creatinine, and urinary calcium/creatinine ratio and NGAL. Participants with euthyroidism showed earlier recovery from AKI than those with ESS. ESS spontaneously disappeared. CONCLUSIONS: ESS is associated with T1DM onset severity and spontaneously disappears. ESS delayed the recovery from AKI. IMPACT: This is the first longitudinal study describing in detail the relationship between clinical/metabolic factors at type 1 diabetes mellitus (T1DM) onset and thyroid hormones, with particular attention to the relationship between diabetic ketoacidosis (DKA)-related kidney function impairment and euthyroid sick syndrome (ESS). Participants with more severe T1DM onset presentation both in terms of metabolic derangement and kidney function impairment had an increased prevalence of ESS. Children with ESS had a slower recovery from acute kidney injury compared with those without ESS. ESS spontaneously disappeared in all participants.

Early detection of thiamine deficiency by non-thyroidal illness syndrome in a hemodialysis patient.

An 88-year-old male patient on maintenance hemodialysis (HD) therapy experienced gradual losses in appetite and liveliness during the course of 1 month. Physical examinations revealed no abnormalities. However, blood testing indicated non-thyroidal illness syndrome (NTIS) typically observed in patients with severe illness, with serum levels of thyroid stimulating hormone, free triiodothyronine, and free thyroxine of 0.17 µIU/mL, < 1.0 pg/mL, and 0.23 ng/dL, respectively. Brain magnetic resonance imaging to exclude the possibility of central hypothyroidism unexpectedly displayed slight abnormalities inside of the thalami that were characteristic of Wernicke's encephalopathy. Additional examination disclosed low serum thiamine of 20 ng/mL. Thiamine injections of 100 mg at every HD treatment rapidly restored his appetite, liveliness, and NTIS findings. HD patients are at a particularly high risk of thiamine deficiency (TD) and associated severe symptoms due to losses of thiamine during HD sessions. However, its non-specific initial symptoms, including decreases in appetite and liveliness, as well as undetectability in routine blood tests complicate early detection, resulting in underdiagnosis and more severe outcomes. In the present case, TD manifested only as non-specific symptoms and was ultimately revealed by the presence of NTIS, which was resolved with thiamine supplementation. Thus, NTIS might assist in the early detection of TD as an initial sign in HD patients.

Low T3 Syndrome on Admission and Response to Nutritional Support in Malnourished Medical Inpatients.

CONTEXT: During illness, deiodination of thyroxine (T4) to triiodothyronine (T3) is downregulated. This is called "low T3 syndrome", an adaptive metabolic mechanism to reduce energy expenditure and prevent catabolism. OBJECTIVE: We aimed to investigate the prognostic role of low T3 syndrome in patients at nutritional risk regarding mortality, clinical outcomes, and response to nutritional support. METHODS: This is a secondary analysis of the Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), a randomized controlled, Swiss, multicenter trial comparing effects of individualized nutritional support with usual care in adult medical inpatients at nutritional risk. The primary endpoint was all-cause mortality over 30, 180 days, and 5 years. RESULTS: We had complete data including fT3 concentration of 801/2028 (39.5%) patients from the initial trial. Of these 492 (61.4%) had low T3 syndrome (fT3 < 3.2 pmol/L). Low T3 syndrome was associated with higher mortality over 30 days (adjusted hazard ratio 1.97, 95% CI 1.17-3.31, P = .011) and other adverse clinical outcomes. Nutritional support only lowered mortality in the group of patients with low T3 syndrome but not in those without low T3 syndrome (adjusted odds ratio of nutritional support of 0.82 [95% CI 0.47-1.41] vs 1.47 [95% CI 0.55-3.94]). This finding, however, was not significant in interaction analysis (P for interaction = .401). CONCLUSION: Our secondary analysis of a randomized trial suggests that medical inpatients at nutritional risk with low T3 syndrome have a substantial increase in mortality and may show a more pronounced beneficial response to nutritional support interventions.

Different Hypothalamic Mechanisms Control Decreased Circulating Thyroid Hormone Levels in Infection and Fasting-Induced Non-Thyroidal Illness Syndrome in Male Thyroid Hormone Action Indicator Mice.

Background: Non-Thyroidal Illness Syndrome (NTIS) caused by infection or fasting is hallmarked by reduced circulating thyroid hormone (TH) levels. To better understand the role of local TH-action in the development of NTIS, we assessed tissue-specific changes of TH signaling in Thyroid Hormone Action Indicator (THAI) mice. Methods: NTIS was induced in young adult THAI mice by bacterial lipopolysaccharide (LPS)-administration or by 24 or 48 hours' fasting. Tissue-specific TH-action was assessed by the detection of changes of the Luciferase reporter of THAI mice with quantitative polymerase chain reaction along with tissue-specific examination of regulators of TH metabolism and signaling. Age dependence of revealed alterations of hypothalamic TH-action was also studied in 1-year-old male THAI mice. Results: LPS-treatment increased TH-action in the hypothalamic arcuate nucleus-median eminence (ARC-ME) region preceded by an increase of type 2 deiodinase (D2) expression in the same region and followed by the suppression of proTrh expression in the hypothalamic paraventricular nucleus (PVN). In contrast, LPS decreased both TH-action and D2 activity in the pituitary at both ages. Tshß expression and serum free thyroxine (fT4) and free triiodothyronine (fT3) levels decreased in LPS-treated young adults. Tshß expression and serum fT4 levels were not significantly affected by LPS treatment in aged animals. In contrast to LPS treatment, TH-action remained unchanged in the ARC-ME of 24 and 48 hours fasted animals accompanied with a modest decrease of proTrh expression in the PVN in the 24-hour group. Tshß expression and fT3 level were decreased in both fasted groups, but the fT4 decreased only in the 48 hours fasted animals. Conclusions: Although the hypothalamo-pituitary-thyroid (HPT) axis is inhibited both in LPS and fasting-induced NTIS, LPS achieves this by centrally inducing local hyperthyroidism in the ARC-ME region, while fasting acts without affecting hypothalamic TH signaling. Lack of downregulation of Tshß and fT4 in LPS-treated aged THAI mice suggests age-dependent alterations in the responsiveness of the HPT axis. The LPS-induced tissue-specific hypo-, eu-, and hyperthyroidism in different tissues of the same animal indicate that under certain conditions TH levels alone could be a poor marker of tissue TH signaling. In conclusion, decreased circulating TH levels in these two forms of NTIS are associated with different patterns of hypothalamic TH signaling.