Non-thyroidal illness syndrome and SARS-CoV-2-associated multisystem inflammatory syndrome in children.

PURPOSE: COVID-19 disease may result in a severe multisystem inflammatory syndrome in children (MIS-C), which in turn may alter thyroid function (TF). We assessed TF in MIS-C, evaluating its impact on disease severity. METHODS: We retrospectively considered children admitted with MIS-C to a single pediatric hospital in Milan (November 2019-January 2021). Non-thyroidal illness syndrome (NTIS) was defined as any abnormality in TF tests (FT3, FT4, TSH) in the presence of critical illness and absence of a pre-existing hormonal abnormality. We devised a disease severity score by combining severity scores for each organ involved. Glucose and lipid profiles were also considered. A principal component analysis (PCA) was performed, to characterize the mutual association patterns between TF and disease severity. RESULTS: Of 26 (19 M/7F) patients, median age 10.7 (IQR 5.8-13.3) years, 23 (88.4%) presented with NTIS. A low FT3 level was noted in 15/23 (65.3%), while the other subjects had varying combinations of hormone abnormalities (8/23, 34.7%). Mutually correlated variables related to organ damage and inflammation were represented in the first dimension (PC1) of the PCA. FT3, FT4 and total cholesterol were positively correlated and characterized the second axis (PC2). The third axis (PC3) was characterized by the association of triglycerides, TyG index and HDL cholesterol. TF appeared to be related to lipemic and peripheral insulin resistance profiles. A possible association between catabolic components and severity score was also noted. CONCLUSIONS: A low FT3 level is common among MIS-C. TF may be useful to define the impact of MIS-C on children's health and help delineate long term follow-up management and prognosis.

Combined use of low T3 syndrome and NT-proBNP as predictors for death in patients with acute decompensated heart failure.

BACKGROUND: In patients with established HF, low triiodothyronine syndrome (LT3S) is commonly present, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a useful marker for predicting death. This study was aimed to evaluate the prognostic value of LT3S in combination with NT-proBNP for risk of death in patients with heart failure (HF). METHODS: A total of 594 euthyroid patients hospitalized with acute decompensated HF were enrolled by design. Of these patients, 27 patients died during hospitalization and 100 deaths were identified in patients discharged alive during one year follow-up. Patients were divided into 2 groups on the base of the reference ranges of free T3 (FT3) levels: LT3S group (FT3 < 2.3pg/mL, n = 168) and non-LT3S group (FT3 ≥ 2.3pg/mL, n = 426). RESULTS: In multivariable Cox regression, LT3S was significantly associated with 1 year all-cause mortality (adjusted hazard ratio, 1.85; 95 % confidence interval [CI], 1.21 to 2.82; P = 0.005), but not significant for in-hospital mortality (adjusted hazard ratio, 1.58; 95 % CI, 1.58 to 2.82; P = 0.290) after adjustment for clinical variables and NT-proBNP. Addition of LT3S and NT-proBNP to the prediction model with clinical variables significantly improved the C statistic for predicting 1 year all-cause mortality. CONCLUSIONS: In patients with acute decompensated HF, the combination of LT3S and NT-proBNP improved prediction for 1 year all-cause mortality beyond established risk factors, but was not strong enough for in-hospital mortality.

Low Free T3 Is Associated With Worse Outcomes in Patients in the ICU Requiring Invasive Mechanical Ventilation.

OBJECTIVE: Critical illness causes a decrease in serum free triiodothyronine (T3) levels. This condition, known as nonthyroidal illness syndrome (NTIS), is associated with poor outcomes. The association of NTIS and outcomes in patients in the intensive care unit (ICU) requiring mechanical ventilation has not been well studied. This study aimed to determine the impact of NTIS on the outcomes of these patients. METHODS: This prospective study included 162 patients in the ICU who underwent mechanical ventilation. Serum free T3 levels were tested on the day of initiation of mechanical ventilation. The rates of in-hospital mortality and ventilator-free days (VFDs) at day 28 after the initiation of mechanical ventilation were compared between patients with low (<2.3 pg/mL) and normal (≥2.3 pg/mL) free T3 levels. Patients who died while on mechanical ventilation were assigned a VFD of 0. RESULTS: Low T3 was present in 60% of study patients. The in-hospital mortality rate of the entire cohort was 39%, and the mean and median VFDs at day 28 were 13.5 and 21 days, respectively. Compared to patients with normal free T3, patients with low free T3 had higher in-hospital mortality (52% vs 19%, P < .001) and less mean and median VFDs at day 28 (10.7 vs 18 and 0 vs 23, respectively. P < .001 for both mean and median VFDs). CONCLUSIONS: The presence of low T3 due to NTIS in patients in the ICU requiring mechanical ventilation is associated with poor outcomes.

An update on non-thyroidal illness syndrome.

The non-thyroidal illness syndrome (NTIS) was first reported in the 1970s as a remarkable ensemble of changes in serum TH (TH) concentrations occurring in probably any severe illness. Ever since, NTIS has remained an intriguing phenomenon not only because of the robustness of the decrease in serum triiodothyronine (T3), but also by its clear correlation with morbidity and mortality. In recent years, it has become clear that (parenteral) feeding in patients with critical illness should be taken into account as a major determinant not only of NTIS but also of clinical outcome. Moreover, both experimental animal and clinical studies have shown that tissue TH concentrations during NTIS do not necessarily reflect serum low TH concentrations and may decrease, remain unaltered, or even increase according to the organ and type of illness studied. These differential changes now have a solid basis in molecular studies on organ-specific TH transporters, receptors and deiodinases. Finally, the role of inflammatory pathways in these non-systemic changes has begun to be clarified. A fascinating role for TH metabolism in innate immune cells, including neutrophils and monocytes/macrophages, was reported in recent years, but there is no evidence at this early stage that this may be a determinant of susceptibility to infections. Although endocrinologists have been tempted to correct NTIS by TH supplementation, there is at present insufficient evidence that this is beneficial. Thus, there is a clear need for adequately powered randomized clinical trials (RCT) with clinically relevant endpoints to fill this knowledge gap.

Determinants of deranged thyroid function parameters in children admitted for management of diabetic ketoacidosis/diabetic ketosis.

BACKGROUND: Euthyroid sick syndrome (ESS) frequently arises in children admitted with diabetic ketoacidosis/diabetic ketosis (DKA/DK). This study evaluates the interplay of various metabolic factors with occurrence of deranged thyroid function tests in children suffering from DKA/DK. METHODS: 98 DKA and 96 DK pediatric patients were selected from hospital records. Those on thyroxine replacement, with overt hypothyroidism, or with positive anti-thyroperoxidase (TPO) antibody were excluded. Tests for liver function, renal function, lipid profile, serum osmolarity, thyroid function, c-peptide levels, and glycosylated hemoglobin were done on all patients. Children were divided into euthyroid (n = 88) and ESS groups (n = 106). RESULTS: The ESS group had a higher level of white blood cell count (WBC), plasma glucose (PG), beta-hydroxybutyric acid (ß-HB), triglyceride (TG), anion gap (AG), glycosylated hemoglobin (HbA1c) and a lower level of HCO3-, prealbumin (PA), and albumin (ALB) compared with the euthyroid group (P < 0.05). Free T3 (FT3) levels were significantly correlated to ß-HB, HCO3-, AG, PA, and HbA1c (r = - 0.642, 0.681, - 0.377, 0.581, - 0.309, respectively; P < 0.01). Free T4 (FT4) levels were significantly correlated to ß-HB, HCO3-, and ALB levels (r = - 0.489, 0.338, 0.529, respectively; P < 0.01). TSH levels were significantly affected by HCO3- only (r = - 0.28; P < 0.01). HCO3- level was the most important factor deciding euthyroid or ESS on logistic regression analysis (OR = 0.844, P = 0.004, 95%CI = 0.751-0.948). CONCLUSIONS: Lower levels of free thyroid hormones and occurrence of ESS were associated with a higher degree of acidosis in children with DKA/DK.

The Role of Thyroid Hormones in Heart Failure.

Cardiovascular diseases are the leading cause of death worldwide. Heart failure is the terminal manifestation of cardiovascular diseases, and its morbidity and mortality remain high. The prevalence of heart failure with preserved ejection fraction (HFpEF) among heart failure patients remains uncertain. However, recent studies have found that it ranged from 40 to 71%. There is still no effective treatment for HFpEF. Thyroid hormones (TH) have central regulatory actions in the cardiovascular system, particularly in the heart. Changes in plasmatic or tissue thyroid hormone levels are associated with significant alterations in cardiovascular function. A significant proportion of patients with heart failure presents some form of thyroid dysfunction including hypothyroidism, hyperthyroidism, and low T3 syndrome. Furthermore, thyroid hormones can vary at a local level independently of the serum TH levels. This may lead to local cardiac hypothyroidism in heart failure. Based on these findings and the role that TH play in cardiovascular regulation, they were proposed as a potential target for heart failure therapy. Several clinical and experimental studies have shown beneficial effects of TH supplementation. Data from epidemiological studies supports a higher risk of heart failure and a worse prognosis in heart failure patients with low levels of TH. In addition, animal studies and small clinical studies suggest that TH supplementation may improve cardiac function in heart failure. Although further studies are needed to evaluate the safety and efficacy of TH in this context, the available evidence suggests that TH modulation is a promising therapeutic approach to heart failure.

The combination of nonthyroidal illness syndrome and renal dysfunction further increases mortality risk in patients with acute myocardial infarction: a prospective cohort study.

BACKGROUND: Both nonthyroidal illness syndrome and renal dysfunction are associated with increased mortality risk in acute myocardial infarction (AMI). However, it is unclear whether combined NTIS and renal dysfunction further increase mortality risk. Therefore, our aim is to investigate whether combined NTIS and renal dysfunction further increases mortality risk in patients with acute myocardial infarction (AMI). METHODS: A total of 1295 inpatients with AMI were divided into normal group (n = 692), NTIS group (n = 139), renal dysfunction group (n = 304), and combined NTIS and renal dysfunction group (n = 160). Heart function, in-hospital, all-cause and cardiovascular mortality were compared among the four groups. RESULTS: After adjustment for age and sex, left ventricular ejection fraction was significantly lower in the combined group (48 ± 11%) than in the NTIS group (52 ± 10%, P = 0.017), the renal dysfunction group (52 ± 10%, P = 0.001) and the normal group (56 ± 8%, P < 0.001). After controlling for confounding factors, compared with the normal group, the NTIS and the renal dysfunction group represented higher risks of in-hospital mortality (OR: 3.643, P = 0.028; OR:3.135, P = 0.042, respectively), all-cause mortality (HR: 2.138, P = 0.007; HR: 2.050, P = 0.003, respectively), and cardiovascular mortality (HR:2.134, P = 0.042; HR:2.237, P = 0.010, respectively). Compared to those in the NTIS and the renal dysfunction group, the patients in the combined group showed a further increased risk for in-hospital mortality (OR:2.916, P = 0.039; OR:2.487, P = 0.036, respectively), all-cause mortality (HR: 1.939, P = 0.015; HR: 2.020, P = 0.002, respectively) and cardiovascular mortality (HR:2.420, P = 0.010; HR:2.303, P = 0.002, respectively). CONCLUSIONS: Both NTIS and renal dysfunction increase short-term in-hospital mortality, and long-term all-cause and cardiovascular mortality risk in patients with AMI. Furthermore, the coexistence of NTIS and renal dysfunction presents further increased mortality risk in AMI patients.

Low triiodothyronine syndrome and selenium deficiency - undervalued players in advanced heart failure? A single center pilot study.

BACKGROUND: The function of deiodinases - selenoproteins converting thyroid hormones may be disturbed by oxidative stress accompanying heart failure. Selenium (Se) may be used by glutathione peroxidase, leading to a lack of deiodinase and triiodothyronine (T3). The aim of the study was the evaluation of the prevalence and clinical significance of low T3 syndrome in heart failure and the assessment of the association of low fT3 and Se deficiency. METHODS: The study group consisted of 59 consecutive patients hospitalized due to decompensated HFrEF NYHA III or IV. Exclusion criteria were: thyroid dysfunction, severe systemic disease, treatment with amiodarone, steroids or propranolol. Group A included 9 patients with low free T3 (fT3) concentration below 3.1 pmol/L. Group B consisted of the remaining 50 patients with normal fT3 levels. RESULTS: The prevalence of low T3 syndrome was 15.3%. The prevalence of Se deficiency was 74.6%. We demonstrated correlations between fT3 and main clinical variables (i.e. NT-proBNP, LVEF, hsCRP), but we did not find correlation between fT3 and the Se level. Kaplan-Meier survival analysis showed lower survival probability in patients with low fT3 (p < 0.001). CONCLUSIONS: Low T3 syndrome is frequently found in patients with HFrEF and is associated with a poor outcome. We did not identify any significant correlation between Se and fT3 level.

[ABNORMALITIES OF THYROID HORMONE METABOLISM DURING COMMUNITY‒ACQUIRED PNEUMONIA: NONTHYROIDAL ILLNESS SYNDROME AND INTRACELLULAR IODINE DISTRIBUTION IN CHILDREN].

The aim of the study ‒ to investigate the changes of thyroid function and to reveal the relationship in between intracellular distribution of iodine in the blood with the severity of the course of pneumonia in children. We investigated 70 patients in age 6-14 years with moderate and severe CAP and 35 healthy children. The levels of free thyroxine (fT4), free triiodo-thyronine (fT3) and thyroid stimulating hormone, thyroid gland ultrasound and urinary iodine were estimated. Inorganic iodine, total and organificated iodine was investigated. The article presents that severe pneumonia in children is characterized by a transient low level of fT3 2,89 pmol/L (p˂0,05). In a dynamics initially low levels of fT3 raise up to normal data. The general condition and clinical symptoms of the patients was improving after treatment of pneumonia and thyroid status was normalized. Mild iodine deficiency has been established in all children. The intracellular pool of iodine with severe pneumonia showed an inverse relationship between the levels of iodine distribution for organificated and inorganic iodine and a close connection between the levels of total and organic iodine (p<0,001). Nonthyroid illness syndrome developed for patients with severe community-acquired pneumonia. The revealed changes in indices of the intracellular pool of iodine and its distribution in the body are directly proportional to the severity of CAP.

[Euthyroid sick syndrome: an important clinical problem].

Despite absence of thyroid disease, patients with non-thyroidal illness frequently have changes in serum thyroid hormone measurements that may suggest thyroid dysfunction. These abnormalities include low serum triiodothyronine, high reverse triiodothyronine and usually normal or inappropriately low thyrotropin and thyroxine levels. The degree of thyroid function impairment correlates with disease severity and low levels of thyroid hormones, particularly thyroxine, predict a poor prognosis. Considerable controversy exists on whether the fall in thyroid hormone levels is adaptive and simply a normal, physiologic response to conserve energy, or whether it is maladaptive and requires treatment. Interpretation of thyroid function tests in the critically ill patient can be difficult and differential diagnosis of euthyroid sick syndrome is challenging, particularly in patients in whom no test results from before the onset of a critical illness are available. In recent years, some questions associated with euthyroid sick syndrome have been better understood. The purpose of this article is to review the present state of knowledge on the pathogenesis, diagnosis and clinical consequences of euthyroid sick syndrome to discuss pros and cons of its treatment.

Role of enteral nutrition in nonthyroidal illness syndrome: a retrospective observational study.

BACKGROUND: The nonthyroidal illness syndrome (NTIS) is prevalent among patients with enterocutaneous fistula and is associated with poor outcomes. The present study aimed to explore the role of enteral nutrition (EN) therapy on thyroid function among patients with enterocutaneous fistula and NTIS. METHODS: We conducted a retrospective observational study among patients with enterocutaneous fistula between January 2013 and April 2014. All enrolled patients received EN therapy. Thyroid function and other parameters were measured. RESULTS: After administration of 4 weeks of EN therapy, NTIS was resolved in 66 patients (Group A), while it persisted in 14 patients (Group B). The overall treatment success rate was 82.50 %. There were no significant differences between groups A and B at baseline for all parameters, except for the time from admission to start of EN therapy. The logistic analysis revealed that the time from admission to start of EN therapy was a significant independent indicator for achieving resolution of NTIS in our cohort. CONCLUSIONS: This retrospective observational cohort study demonstrated that EN therapy can aid in the resolution of NTIS among patients with enterocutaneous fistula. These findings confirm the benefit of EN in the treatment of enterocutaneous fistula.

Left ventricular function by speckle-tracking echocardiography in patients with low-T3 syndrome and acute myocardial infarction.

BACKGROUND AND OBJECTIVE: Low-T3 syndrome is common in patients with acute myocardial infarction (AMI). Recent experimental and clinical data have suggested a potential negative impact of low-T3 syndrome on myocardial function in patients with AMI. The aim of this study was to assess left ventricular (LV) myocardial function in patients with low-T3 syndrome and to investigate the association between hormonal profile and the severity of LV dysfunction using speckle-tracking echocardiography (STE). MATERIALS AND METHODS: In 130 patients with first-onset ST-segment elevation acute myocardial infarction (STEMI), conventional 2D and speckle-tracking echocardiography within 48-72h after the hospitalization was performed, and blood samples for TSH, fT4, fT3, and anti-TPO levels were obtained to investigate thyroid hormone production within 24h and on the fourth day after the onset of STEMI symptoms. RESULTS: The patients were divided into two groups according to their serum level of fT3: group 1 with fT3 concentration below 3.2pmol/L (n=34) and group 2 with normal fT3 (>3.2pmol/L) level (n=96). LV ejection fraction (EF) tended to be lower in the low fT3 group. The systolic longitudinal strain did not differ between the groups, but the late diastolic longitudinal strain rate was lower in group 1 (P=0.011). The systolic basal LV rotation positively correlated with the level of fT3 (r=0.4; P<0.001), while a negative correlation was detected between myocardial rotational parameters - systolic apical rotation (r=-0.2; P<0.05), torsion (r=-0.3; P<0.001), and diastolic apical rotation rate (r=-0.3; P<0.01) - and fT3 levels. CONCLUSIONS: The late diastolic longitudinal LV strain rate and LV rotation evaluated by speckle-tracking echocardiography were impaired in patients with low-T3 syndrome after AMI.

Thyroid function, cardiovascular events, and mortality in diabetic hemodialysis patients.

BACKGROUND: In dialysis patients, the prevalence of thyroid disorders and their impact on specific cardiovascular (CV) events and mortality are largely unknown. The aim of the present study was to analyze whether subclinical thyroid disorders were associated with CV events and mortality. STUDY DESIGN: Prospective multicenter cohort study. SETTING & PARTICIPANTS: Thyroid status and clinical outcomes were explored in 1,000 diabetic hemodialysis patients from 178 centers in Germany. PREDICTOR: Thyroid status, defined by the following cutoff values: euthyroidism (thyrotropin [TSH], 0.30-4.0 mIU/L; free triiodothyronine [T3], 2.7-7.6 pmol/L; and free thyroxine [T4], 11.0-24.0 pmol/L), subclinical hyperthyroidism (TSH<0.3 mIU/L and free T3/free T4 within reference ranges), subclinical hypothyroidism (TSH, 4.1-15.0 mIU/L and free T3/free T4 within reference ranges), euthyroid sick syndrome (free T3<2.7 pmol/L and TSH/free T4 low or within reference ranges). OUTCOMES: During 4 years' follow-up, prespecified adjudicated end points were determined: sudden cardiac death, myocardial infarction, stroke, combined CV events, and overall mortality. Short-term effects within the first 12 months were contrasted to long-term effects (years 2-4). MEASUREMENTS: TSH, free T3, and free T4 levels at baseline. RESULTS: Euthyroidism was present in 78.1% of patients; subclinical hyperthyroidism, in 13.7%; and subclinical hypothyroidism, in 1.6%. Euthyroid sick syndrome was exhibited by 5.4% of patients. The adjusted short-term risk of sudden cardiac death was more than doubled (HR, 2.03; 95% CI, 0.94-4.36) in patients with subclinical hyperthyroidism, and similarly for patients with euthyroid sick syndrome (HR, 2.74; 95% CI, 0.94-7.98) compared with patients with euthyroidism. Short-term mortality was increased almost 3-fold for patients with euthyroid sick syndrome (HR, 2.97; 95% CI, 1.66-5.29), but this effect was not seen in the long term. Subclinical hypothyroidism was not associated with CV events or all-cause mortality. Risks of stroke and myocardial infarction were not affected meaningfully by thyroid disorders. LIMITATIONS: Observational study design. CONCLUSIONS: Sudden cardiac death may be influenced by subclinical hyperthyroidism and euthyroid sick syndrome in the short term. Furthermore, euthyroid sick syndrome is associated strongly with mortality in hemodialysis patients. Regular assessment of thyroid status may help estimate the cardiac risk of dialysis patients.

An update for the controversies and hypotheses of regulating nonthyroidal illness syndrome in chronic kidney diseases.

Nonthyroidal illness syndrome (NTIS) is widely found in the patients with chronic kidney disease (CKD) or critical illness. However, the exact pathogenesis and reasonable treatment remain unclear. To identify suitable studies for inclusion in present review, a search for articles using PubMed search engine with combined terms: (thyroid OR hypothyroidism OR hyperthyroidism OR triiodothyronine) AND (glomerulonephritis OR chronic kidney disease OR chronic renal failure OR end stage renal disease OR hemodialysis OR peritoneal dialysis OR kidney transplantation OR renal transplantation) was performed. The bibliographies of relevant articles were also hand searched. The search was updated on November 8, 2013. Mechanisms for the alternations of thyroid hormone concentrations in NTIS are complicated. Inflammatory cytokines and oxidative stress may play pivotal roles in the pathogenesis of NTIS in patients with CKD. It was controversial whether CKD patients with NTIS should be treated with thyroid hormone replacement. N-Acetyl cysteine or sodium bicarbonate may negatively regulate the progress of micro-inflammation in CKD. Large-scale, multi-centered randomized controlled trials should be conducted to verify the NTIS hypothesis in CKD patients.

Nonthyroidal illness syndrome: is it far away from Crohn's disease?

GOALS: This study was designed to investigate the clinical features of nonthyroidal illness syndrome (NTIS) compared with euthyroid patients in Crohn's disease (CD), to explore the etiology of NTIS in CD, to evaluate the clinical outcomes of NTIS patients, and to inspect the correlation of clinical variables and NTIS, and their ability of differentiating NTIS from euthyroid patients. BACKGROUND: NTIS has been described for more than 30 years. However, only few studies focused on the relationship between NTIS and CD. The incidence, underlying pathogenesis, clinical outcomes, and correlation with other inflammatory disease severity and nutritional variables of NTIS in CD have not been completely established. METHODS: Prospectively, 44 CD patients were enrolled. Medical records and various laboratory values (including thyroidal, nutritional, and inflammatory variables) were collected in all participants. RESULTS: The incidence of NTIS in CD was 36.4%. Albumin, Acute Physiology and Chronic Health Evaluation II score, and Crohn's Disease Activity Index score in NTIS group were statistically different from those in euthyroid group. A decreased sum activity of deiodinases and a reduced ratio of TT4/FT4 were observed in NTIS group. Duration of hospitalization was significantly longer for NTIS patients than euthyroid patients. Albumin was confirmed as a protective factor of NTIS in CD. Receiver operating characteristic curve analysis demonstrated the differentiating capacity of albumin, suggesting 37.6 g/L as optimal cut-off value with sensitivity and specificity of 81.3% and 79.2%, respectively. CONCLUSIONS: NTIS was a common complication in CD. NTIS patients showed worse nutrition status and clinical outcome, and more critical disease activity and severity compared with euthyroid patients. A hypodeiodination condition and a potential thyroid-hormone-binding dysfunction may play a role in the etiology of NTIS in CD. Albumin was a meaningful protective and distinguishing marker of NTIS in CD.

[Nonthyroidal illness syndrome in acute bacterial endotoxicosis: pathogenesis and methods of correction].

Nonthyroidal illness syndrome is characterized by alterations of thyroid status inpatients with severe nonthyroidal illness who are clinically euthyroid. Mechanisms of nonthyroidal illness syndrome are poorly understood and controversial. Our investigations on nonthyroidal illness syndrome in acute endotoxicosis revealed two principal mechanisms of its development. The peripheral mechanism is the first to develop and referred to disturbance of thyrocytes secretory cycle due to increase of thyroglobulin synthesis, endocytosis and decrease of its proteolytic cleavage. It manifests with drop of serum thyroxine, not triiodthyronine, and increase of serum thyroid stimulating hormone. The central mechanism is associated with hypothalamic-pituitary hypofunction developed simultaneously with systemic inflammatory response. Rate of supplementation of the peripheral mechanism with the central one accounts for different types of nonthyroidal illness syndrome with high, normal and low serum levels of thyroid stimulating hormone. Our research showed that thyroid hormone replacement in nonthyroidal illness syndrome could only suppress thyroid function. Unlike thyroid hormones administration of thyroid stimulating hormone restores thyroid hormone secretion in nonthyroidal illness syndrome, decreases endotoxinemia and secretion of proinflammatory cytokines and improves liver function.

[Nonthyroidal illness (NTI)].

Thyroxine (T4), a major secretory product of thyroid gland, needs to be converted to 3,5,3'-triiodothyronine (T3) by iodothyronine deiodinases to exert its biological effect. Nonthyroidal illness, also known as low T3 syndrome, is associated with low serum T3 concentrations, which are inversely correlated to the severity of the illness. The patients with nonthyroidal illness do not show compensatory rise in serum TSH concentrations, and sometimes develop low serum T4 and TSH concentrations. It has been postulated that decreased extrathyroidal conversion of T4 to T3 is a responsible mechanism underlying low T3 syndrome. The roles of three types of iodothyronine deiodinases (D1, D2, D3) in the pathophysiology of nonthyroidal illness are discussed.

Elevated Thyroid Autoantibodies Aggravate Stroke Severity in Euthyroidism with Acute Ischemic Stroke.

Introduction: Studies have indicated that immune reactions contribute to endothelial dysfunction and atherosclerosis. It is unclear whether thyroid dysfunction or elevated thyroid autoantibodies are associated with atherosclerosis. Therefore, we investigated the influence of thyroid autoimmunity related to elevated thyroid autoantibodies on functional outcome in euthyroidism with acute ischemic stroke (AIS). Methods: All patients with AIS underwent tests for thyroid function and thyroid antibodies (thyroid peroxidase antibody and thyroglobulin autoantibody). We divided the patients suffering from euthyroidism and AIS into positive thyroid autoantibody and negative thyroid autoantibody groups. Demographic profiles, risk factors, and functional outcomes were compared between the two groups. Results: Out of the total 422 patients, 50 (11.8%) were included in the positive thyroid autoantibody group. The National Institutes of Health Stroke Scale (NIHSS) score at admission and discharge was higher in the positive thyroid autoantibody group than the negative thyroid autoantibody group (P < 0.05). In addition, there was significant difference in the mortality during hospitalizations between the two groups (P < 0.01). Conclusion: This study showed that thyroid autoantibodies aggravate stroke severity in euthyroidism with AIS. We speculate that vascular damage related to thyroid autoimmunity may aggravate the increased risk of unfavorable outcomes, independent of thyroid function.

The nonthyroidal illness syndrome in the non-critically ill patient.

BACKGROUND: The nonthyroidal illness syndrome (NTIS) is a very common clinical entity among hospitalized patients and has been reported in practically every severe illness and acute or chronic stressful event. There is a large body of data associating the presence of NTIS with the severity of the underlying disease. Most of these studies concern intensive care unit (ICU) patients, whereas the non-critically ill patients outside the ICU setting are less well studied. DESIGN: We provide a review of the existing literature focusing on studies examining NTIS in non-critically ill patients and attempt to summarize the pathophysiological pathways underlying the syndrome, its prognostic role, as well as the current intervention studies mainly from a clinical standpoint. RESULTS: The aetiology of the NTIS is multifactorial and varies among different groups of patients. Experimental and clinical findings suggest that inflammatory cytokines are implicated in the pathogenesis of the syndrome, whereas recent evidence re-evaluate the role of deiodinases in thyroid hormone metabolism not only in the periphery but also in the hypothalamus and the pituitary and thus in the alterations accompanying NTIS. Clinical data examining the effectiveness of thyroid hormone supplementation in NTIS remain controversial. CONCLUSIONS: As long as there is no clear evidence of benefit from thyroid hormone replacement and until well-designed studies confirm its efficacy, thyroxine supplementation should not be recommended for the treatment of NTIS.

Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness.

INTRODUCTION: Prolonged critically ill patients reveal low circulating thyroid hormone levels without a rise in thyroid stimulating hormone (TSH). This condition is labeled "low 3,5,3'-tri-iodothyronine (T3) syndrome" or "nonthyroidal illness syndrome (NTI)" or "euthyroid sick syndrome". Despite the low circulating and peripheral tissue thyroid hormone levels, thyrotropin releasing hormone (TRH) expression in the hypothalamus is reduced and it remains unclear which mechanism is responsible. We set out to study whether increased hypothalamic T3 availability could reflect local thyrotoxicosis and explain feedback inhibition-induced suppression of the TRH gene in the context of the low T3 syndrome in prolonged critical illness. METHODS: Healthy rabbits were compared with prolonged critically ill, parenterally fed animals. We visualized TRH mRNA in the hypothalamus by in situ-hybridization and measured mRNA levels for the type II iodothyronine diodinase (D2), the thyroid hormone transporters monocarboxylate transporter (MCT) 8, MCT10 and organic anion co-transporting polypeptide 1C1 (OATP1C1) and the thyroid hormone receptors alpha (TRalpha) and beta (TRbeta) in the hypothalamus. We also measured the activity of the D2 and type III iodothyronine deiodinase (D3) enzymes. RESULTS: In the hypothalamus of prolonged critically ill rabbits with low circulating T3 and TSH, we observed decreased TRH mRNA, increased D2 mRNA and increased MCT10 and OATP1C1 mRNA while MCT8 gene expression was unaltered as compared with healthy controls. This coincided with low hypothalamic thyroxine (T4) and low-normal T3 concentrations, without a change at the thyroid hormone receptor level. CONCLUSIONS: Although expression of D2 and of the thyroid hormone transporters MCT10 and OATP1C1 were increased in the hypothalamus of prolonged critical ill animals, hypothalamic T4 and T3 content or thyroid hormone receptor expression were not elevated. Hence, decreased TRH gene expression, and hereby low TSH and T3 during prolonged critical illness, is not exclusively brought about by hypothalamic thyrotoxicosis, and infer other TRH suppressing factors to play a role.