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.

Higher Caloric Exposure in Critically Ill Patients Transiently Accelerates Thyroid Hormone Activation.

INTRODUCTION: The inflammatory response of critical illness is accompanied by nonthyroidal illness syndrome (NTIS). Feeding has been shown to attenuate this process, but this has not been explored prospectively over time in critically ill patients. OBJECTIVE: To explore the impact of calorie exposure on NTIS over time in critically ill patients. METHODS: Mechanically ventilated patients with systemic inflammatory response syndrome (SIRS) were randomized to receive either 100% or 40% of their estimated caloric needs (ECN). Thyroid hormones were measured daily for 7 days or until intensive care unit discharge or death. Mixed level regression modeling was used to explore the effect of randomization group on plasma triiodothyronine (T3), reverse triiodothyronine (rT3), thyroxine (T4), and thyroid stimulating hormone (TSH), as well as the T3/rT3 ratio. RESULTS: Thirty-five participants (n=19 in 100% ECN; n=16 in 40% ECN) were recruited. Adjusting for group differences in baseline T3/rT3 ratio, the parameters defining the fitted curves (intercept, linear effect of study day, and quadratic effect of study day) differed by randomization group (P = 0.001, P = 0.01, and P = 0.02 respectively). Plots of the fitted curves revealed that participants in the 100% ECN group had a 54% higher T3/rT3 ratio on postintervention day 1 compared with the 40% ECN group, a difference which attenuated over time. This was driven by a 23% higher plasma T3 and 10% lower plasma rT3 levels on postintervention 1. CONCLUSIONS: Higher caloric exposure in NTIS patients transiently attenuates the drop of the plasma T3/rT3 ratio, an effect that is minimized and finally lost over the following 3 days of continued higher caloric exposure.

Nonthyroidal illness in critically ill children.

PURPOSE OF REVIEW: This review summarizes recent literature on nonthyroidal illness syndrome (NTI) and outcome of pediatric critical illness, to provide insight in pathophysiology and therapeutic implications. RECENT FINDINGS: NTI is typically characterized by lowered triiodothyronine levels without compensatory TSH rise. Although NTI severity is associated with poor outcome of pediatric critical illness, it remains unclear whether this association reflects an adaptive protective response or contributes to poor outcome. Recently, two metabolic interventions that improved outcome also altered NTI in critically ill children. These studies shed new light on the topic, as the results suggested that the peripheral NTI component, with inactivation of thyroid hormone, may represent a beneficial adaptation, whereas the central component, with suppressed TSH-driven thyroid hormone secretion, may be maladaptive. There is currently insufficient evidence for treatment of NTI in children. However, the recent findings raised the hypothesis that reactivation of the central NTI component could offer benefit, which should be tested in RCTs. SUMMARY: NTI in critically ill children can be modified by metabolic interventions. The peripheral, but not the central, component of NTI may be a beneficial adaptive response. These findings open perspectives for the development of novel strategies to improve outcome of critical illness in children.

Non-Thyroidal Illness Syndrome in Critically Ill Children: Prognostic Value and Impact of Nutritional Management.

INTRODUCTION: Non-thyroidal illness (NTI), which occurs with fasting and in response to illness, is characterized by thyroid hormone inactivation with low triiodothyronine (T3) and high reverse T3 (rT3), followed by suppressed thyrotropin (TSH). Withholding supplemental parenteral nutrition early in pediatric critical illness (late-PN), thus accepting low/no macronutrient intake up to day 8 in the pediatric intensive care unit (PICU), accelerated recovery compared to initiating supplemental parenteral nutrition early (early-PN). Whether NTI is harmful or beneficial in pediatric critical illness and how it is affected by a macronutrient deficit remains unclear. This study investigated the prognostic value of NTI, the impact of late-PN on NTI, and whether such impact explains or counteracts the outcome benefit of late-PN in critically ill children. METHODS: This preplanned secondary analysis of the Early versus Late Parenteral Nutrition in the Pediatric Intensive Care Unit randomized controlled trial quantified serum TSH, total thyroxine (T4), T3, and rT3 concentrations in 982 patients upon PICU admission versus 64 matched healthy children and in 772 propensity score-matched early-PN and late-PN patients upon admission and at day 3 or last PICU day for shorter PICU stay. Associations between thyroid hormone concentrations upon admission and outcome, as well as impact of late-PN on NTI in relation with outcome, were assessed with univariable analyses and multivariable logistic regression, linear regression, or Cox proportional hazard analysis, adjusted for baseline risk factors. RESULTS: Upon PICU admission, critically ill children revealed lower TSH, T4, T3, and T3/rT3 and higher rT3 than healthy children (p < 0.0001). A more pronounced NTI upon admission, with low T4, T3, and T3/rT3 and high rT3 was associated with higher mortality and morbidity. Late-PN further reduced T4, T3, and T3/rT3 and increased rT3 (p ≤ 0.001). Statistically, the further lowering of T4 by late-PN reduced the outcome benefit (p < 0.0001), whereas the further lowering of T3/rT3 explained part of the outcome benefit of late-PN (p ≤ 0.004). This effect was greater for infants than for older children. CONCLUSION: In critically ill children, the peripheral inactivation of thyroid hormone, characterized by a decrease in T3/rT3, which is further accentuated by low/no macronutrient intake, appears beneficial. In contrast, the central component of NTI attributable to suppressed TSH, evidenced by the decrease in T4, seems to be a harmful response to critical illness. Whether treating the central component with TSH releasing hormone infusion in the PICU is beneficial requires further investigation.

[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.

Enfermedad no tiroidea / Non-thyroidal illness

La enfermedad no tiroidea es una entidad que se presenta frecuentemente en los pacientes que se encuentran cursando algún tipo de enfermedad, ya sea crítica o no; y puede manifestarse aun en ausencia de enfermedad tiroidea subyacente, condicionando cambios en el eje tiroideo. Es importante poder reconocer la enfermedad no tiroidea para hacer diagnóstico diferencial con la patología tiroidea verdadera y evaluar si merece ser tratada. Aún no existe consenso acerca de si la enfermedad no tiroidea representa una respuesta fisiológica a una enfermedad sistémica para que disminuyan los requerimientos de energía o si se trata de una condición adaptativa que induce un estado hipotiroideo que finalmente resulta perjudicial a nivel tisular.

Non-thyroidal illness is a disorder that occurs frequently in patients that are experiencing some kind of illness, whether critical or not. It can manifest even in the absence of thyroid dysfunction, leading to changes in the thyroid axis. It is important to detect Non-Thyroidal Illness in order to establish a differential diagnosis with the true thyroid disease and to determine whether treatment is required. Currently, there is still no consensus on whether Non-Thyroidal Illness is a physiological response to a systemic disease to reduce energy requirements or whether it is an adaptive condition that induces a hypothyroid state that ultimately is harmful at the tissue level.

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.

Non-thyroidal illness in the ICU: a syndrome with different faces.

BACKGROUND: Critically ill patients typically present with low or low-normal plasma thyroxine, low plasma triiodothyronine (T3), increased plasma reverse T3 (rT3) concentrations, in the absence of a rise in thyrotropin (TSH). This constellation is referred to as nonthyroidal illness syndrome (NTI). Although it is long known that the severity of NTI is associated with risk of poor outcomes of critical illness, the causality in this association has not been well investigated. SUMMARY: In this narrative review, the different faces of NTI during critical illness are highlighted. Acute alterations are dominated by changes in thyroid hormone binding, peripheral thyroid hormone uptake, and alterations in the expression and activity of the type-1 and type-3 deiodinases. It was recently shown that at least part of these acute changes are brought about by concomitant macronutrient restriction, and this part appears adaptive and beneficial. However, the face of the NTI in the prolonged phase of critical illness is different, when patients are fully fed but continue to depend on intensive medical care. In that prolonged phase of illness, hypothalamic thyrotropin releasing hormone (TRH) expression is suppressed and explains reduced TSH secretion and whereby reduced thyroidal hormone release. During prolonged critical illness, and in the presence of adequate nutrition, several tissue responses could be interpreted as compensatory to low thyroid hormone availability, such as increased expression of monocarboxylate transporters, upregulation of type-2 deiodinase activity, and increased sensitivity at the receptor level. Infusing hypothalamic releasing factors in these prolonged critically ill patients can reactivate the thyroid axis and induce an anabolic response. CONCLUSIONS: It is clear that the name "NTI" during critical illness refers to a syndrome with different faces. Tolerating the early "fasting response" to critical illness and its concomitant changes in thyroid hormone parameters appears to be wise and beneficial. This thus applies to the NTI present in the majority of the patients treated in intensive care units. However, the NTI that occurs in prolonged critically ill patients appears different with regard to both its causes and consequences. Future studies should specifically target this selected population of prolonged critically ill patients, and, after excluding iatrogic drug interferences, investigate the effect on outcome of treatment with hypothalamic releasing factors in adequately powered randomized controlled trials.

[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.

Common endocrine issues in the pediatric intensive care unit.

Thyroid hormone is central to normal development and metabolism. Abnormalities in thyroid function in North America often arise from autoimmune diseases, but they rarely present as critical illness. Severe deficiency or excess of thyroid hormone both represent life-threatening disease, which must be treated expeditiously and thoroughly. Such deficiencies must be considered, because presentation may be nonspecific.

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.

Thyroid function during critical illness.

The metabolic support of the critically ill patient is a relatively new target of active research and little is as yet known about the effects of critical illness on metabolism. The nonthyroidal illness syndrome, also known as the low T3 syndrome or euthyroid sick syndrome, describes a condition characterized by abnormal thyroid function tests encountered in patients with acute or chronic systemic illnesses. The laboratory parameters of this syndrome include low serum levels of triiodothyronine (T3) and high levels of reverse T3, with normal or low levels of thyroxine (T4) and normal or low levels of thyroid-stimulating hormone (TSH). This condition may affect 60 to 70% of critically ill patients. The changes in serum thyroid hormone levels in the critically ill patient seem to result from alterations in the peripheral metabolism of the thyroid hormones, in TSH regulation, in the binding of thyroid hormone to transport-protein and in receptor binding and intracellular uptake. Medications also have a very important role in these alterations. Hormonal changes can be seen within the first hours of critical illness and, interestingly, these changes correlate with final outcome. Data on the beneficial effect of thyroid hormone treatment on outcome in critically ill patients are so far controversial. Thyroid function generally returns to normal as the acute illness resolves.

Low triiodothyronine syndrome: a prognostic marker for outcome in sepsis?

There is ongoing controversy as to whether hormonal changes of the euthyroid sick syndrome are predictors of poor outcome in sepsis and critical illness. In this prospective study, the prognostic accuracy of thyroid hormone levels in 103 critically ill adult patients on admission and during follow up in a medical intensive care unit (ICU) was assessed and was compared to clinical risk scores, namely, the acute physiology and chronic health evaluation and the simplified acute physiology score. Median T3 levels on admission to the ICU were lower in the 53 septic cases [0.9 nmol/l (IQR 0.6-1.1)] as compared with the 50 patients with a systemic inflammatory response syndrome [1.2 nmol/l (IQR 0.8-1.4), P < 0.001]. The lowest T3 levels were found in patients with severe sepsis [0.8 nmol/l (IQR 0.55-0.95)] and septic shock [0.8 nmol/l (IQR 0.6-1.0)]. There was no difference in T3 and free thyroxin (fT4) levels on admission in non-survivors compared with survivors overall and in subgroups of patients with SIRS and sepsis. During the follow up, fT4 levels decreased significantly in non-survivors, while they increased in survivors [fT4 difference -1.3 (IQR -2.5 to 0.2) vs. 0.8 (IQR -0.85 to 4.1), P = 0.003]. In addition, on the day of death, non-survivors had lower T3 and fT4 levels as compared with survivors (P = 0.04 and P = 0.02). T3 and fT4 levels on admission were not prognostic in this cohort of critically ill patients. A decrease in fT4 levels in the course of disease, however, may point to adverse outcome.

The role of thyroid dysfunction in the critically ill: a review of the literature.

During critical illness, patients with no known history of thyroid disorders may experience multiple alterations in their serum thyroid hormone levels. Such alterations have been termed sick euthyroid syndrome or, more recently, non-thyroidal illness syndrome (NTIS). The laboratory parameters of NTIS usually include low serum levels of triiodothyronine (T3), normal or low serum levels of thyroxine (T4) and normal or low serum levels of thyroid-stimulating hormone (TSH). The magnitude of the alteration in thyroid function correlates with the severity of the illness and its outcomes in critically ill patients with NTIS. The pathogenetic mechanisms involved in NTIS include a decreased conversion of T4 to T3 in extrathyroidal tissues and alterations in thyroid hormones' binding to serum proteins. In cases of protracted critical illness, a decrease in the pulsatile frequency of TSH secretion, resulting from reduced thyrotropin-re leasing hormone (TRH) release by the hypothalamus, may also occur. Several medications or clinical conditions that are commonly present in critically ill patients may be responsible for lowering serum concentrations of thyroid hormone. Among those who study the condition, the question of whether NTIS is a protective adaptation of the organism to illness or a maladaptive response to a stressful insult remains unanswered. In either case, thyroid hormone abnormalities are likely to play a role in the critically ill patient.However, there is currently no convincing evidence to suggest that restoring physiological thyroid hormone concentrations in unselected patients with NTIS would be beneficial.

Nonthyroidal illness syndrome in children.

Neuroendocrine changes in the hypothalamic-pituitary-thyroid axis during critical illness result in nonthyroidal illness syndrome (NTIS) characterized by abnormal thyrotropin (TSH) and thyroid hormone levels. Studies looking at the natural history of neuroendocrine changes during critical illness have revealed the presence of NTIS. NTIS has been described in a variety of patient settings. Many studies have tried to uncover the pathophysiology behind NTIS and several theories are proposed. Whether NTIS requires treatment or intervention is still controversial and the results of the treatment studies are arguably mixed. Whether implicitly stated or not, the underlying purpose of all the natural history, pathophysiology, or treatment studies is to determine whether NTIS is adaptive or maladaptive. Some studies have illustrated a correlation between illness severity and the degree of NTIS but a cause and effect relationship is still elusive. The human studies can be divided between those with either adult or pediatric subjects, with much less data available in the latter. This review examines the available literature on NTIS with an emphasis on the pediatric literature.

Euthyroid pretibial myxedema and EMO syndrome.

EMO syndrome is a rare extrathyroid syndrome, seen in only 1% of patients affected by extrathyroid complications of Graves' disease. A 73-year-old woman presented with a 1-year history of asymptomatic local swellings on her legs and feet. Physical examination revealed moderate proptosis and multiple, firm subcutaneous nodules of 1 to 5 cm in diameter located on the anterior and medial aspects of the shins and on feet. The patient had a history of bilateral knee arthroplasty 5 years ago. Histopathologic examination showed deposition of mucin and perivascular lymphocytic infiltration in the dermis. Dermatologic and pathologic findings were consistent with pretibial myxedema. Laboratory tests showed normal thyroid stimulating hormone (TSH) and serum free T3 and T4 levels. The TSH receptor antibody titer was elevated. Thus, with all these findings she was diagnosed with exophthalmia, myxedema, and hypertrophic osteoarthropathy (EMO) syndrome. The lesions were completely treated with three monthly intralesional corticosteroid injections and at the 4-month follow-up no recurrence was observed. Only three euthyroid cases with pretibial myxedema have been reported in the literature. Patients that have asymptomatic pretibial nodular or plaque lesions should be investigated with an ophthalmologic examination and laboratory workup to clarify a possible underlying thyroid gland disease and EMO syndrome.