Thyroid hormone disorders and sepsis

Abstract

Sepsis is a systemic inflammatory response syndrome with high mortality, which results from severe infection and can lead to secondary organ dysfunction. It is one of the most common cause of death in intensive care unit. Clinical reports have shown that sepsis was often accompanied by thyroid dysfunction, which is called “low triiodothyronine (T3)” syndrome and characterized by decreased blood total T3 and free T3, and by normal or decreased thyroxine (T4) and thyroid stimulating hormone (TSH). This syndrome may greatly affect the prognosis of patients with sepsis. The main purpose of this review is to illustrate the role of thyroid hormone disorder in the development and prognosis of sepsis.

Keywords

Sepsis thyroid hormone low T3 syndrome organ dysfunction

1. Introduction

Sepsis is a systemic inflammatory response syndrome caused by severe infection. It is a main cause of death in intensive care units and its mortality rate is as high as thirty to seventy percent [1]. The main mechanisms of sepsis may involve systemic inflammatory network effects, complex gene polymorphisms, immune dysfunction, dysfunction of blood coagulation and anti-coagulation, tissue injury and etc. [2–4]. It has been shown that critical illness including sepsis were often accompanied by alterations in levels or functions of hormones, such as thyroid hormones, insulin, adrenal glucocorticoids, etc. Alterations in thyroid hormone is called low triiodothyronine (T3) syndrome, which were associated with mortality of sepsis [5–7]. Low T3 syndrome is manifested by decreased serum total T3 (TT3), free T3 (FT3), and total thyroxine (TT4), normal or low free T4 (FT4) and thyroid stimulating hormone (TSH). Changes in levels of serum thyroid hormones without concomitant thyroid diseases are also known as non-thyroidal illness syndrome (NTIS). Low T3 syndrome in sepsis is mainly caused by acute severe inflammation, which can impair the function of hypothalamic- pituitary-thyroid axis [8,9]. Serum TT4 and FT4 levels may significantly decrease as sepsis progresses [10].

2. Thyroid hormone disorders and prognosis of sepsis

Levels of serum T3 has been shown to be associated with the mortality of septic shock. Yildizdas et al. reported first that twenty-one cases of pediatric septic shock patients in critical care unit had significantly lower levels of plasma TT3, FT3, TT4 and FT4 than non-septic shock patients and healthy children. Furthermore, fifteen patients who died of sepsis had significantly lower thyroid hormone levels than the survivors [11]. Another study on twenty cases of adult septic shock showed similar results [12]. Preliminary findings also suggested that serum T3 level was negatively related to the mortality of septic shock patients [13,14]. Patients with lower levels of serum FT3 and FT4 often had higher Acute Physiology and Chronic Health Evaluation (APACHE) II score and worse prognosis [15]. Moreover, exogenous T3 supplement could decrease mortality of surgical patients with sepsis [16].

3. Thyroid hormones and immune function

Thyroid hormones are closely related to immune function. As a source of iodine, thyroid hormones plays an important role in the antimicrobial system of myeloperoxidase-hydrogen peroxide-halide in neutrophils. With the degradation of thyroid hormones, concentration of iodide was increased in neutrophils, thereby enhancing the bactericidal activity of the neutrophils [17]. Fernandez and Videla also reported that the activity of NADPH oxidase and myeloperoxidase was significantly augmented by feeding rats with T3 [18]. Otherwise, Inan et al. demonstrated that thyroid hormone replacement therapy in septic animal models could enhance phagocytic activity of neutrophils, suggesting the relationship between thyroid hormones and antibacterial activity of the body [19]. In addition to neutrophils, thyroid hormones could also influence function and activity of other immune cells. Alamino found that T3 could augment activation and expansion of cytotoxic lymphocyte T stimulated by dendritic cells [20]. Therefore, normal thyroid hormone level is necessary for maintaining immune function of the whole body.

4. Thyroid hormones and coagulation function

In sepsis, a large number of pro-inflammatory and anti-inflammatory mediators were produced, which can induce disorders in hemodynamics and blood coagulatory–anticoagulatory function. Dysfunction of coagulation-anticoagulatory system favorites development of sepsis, particular septic organ dysfunctions. For example, pro-inflammatory tumor necrosis factor-α (TNF-α), which can induce damage of endothelium, could activate both endogenous and exogenous coagulation pathways, leading to occurrence of disseminated intravascular coagulation (DIC) [4,21,22]. Anti-thrombin III is a potent inhibitor of the coagulation cascade. It plays an important role in maintaining the balance between coagulatory and anticoagulatory function in septic patients. It has been shown that level of plasma anti-thrombin III can be used to evaluate the prognosis of patients with septic shock [23]. Furthermore, supplement of T3 could protect septic patients from DIC through increasing level of anti-thrombin III, and thus improve prognosis and reduce the mortality of these patients [24].

5. Thyroid hormones and septic cardiac dysfunction

Septic cardiac dysfunction is characterized by decreases in left ventricular ejection fraction (LVEF), ventricular diastolic function, maximum ventricular systolic pressure/end-systolic volume, whereas increase of ventricular end-diastolic pressure, resulting in decreased cardiac output and blood pressure. About forty percent septic patients had cardiac dysfunction. Severity of cardiac dysfunction was shown to be correlated with the prognosis of sepsis. Myocardial mitochondrial dysfunction, energy metabolism disorder, myocardial intracellular calcium circulation disorder, apoptosis of myocardial cells have been shown to be involved in the pathogenesis of septic cardiac dysfunction [25–27]. Serum from septic patients could stimulate expression of transcription factors as STAT1, IRF1and NF-κB, and induce apoptosis of myocardial cells through MAPK pathway [28].

Appropriate level of thyroid hormones is essential for normal cardiac growth, and for the maintenance of normal heart electrical activity and systolic/diastolic function. T3 can bind to its nuclear receptor to promote expression of sarcoplasmic reticulum calcium ATPase 2 (SERCA2) and α-myosin heavy chain (α-MHC). T3 can also bind to its cytoplasm receptor, augment the activity of ${Na}^{+} / K^{+}$ -ATPase and ${Ca}^{2 +}$ -ATPase in myocardial cells through PI3K-Akt-mTOR signaling pathway, and increase the expression and opening of L- ${Ca}^{2 +}$ channel, leading to increased extracellular calcium influx and myocardial contractility [29]. Moreover, thyroid hormone can increase the density of β receptor on the membrane of myocardial cells and the sensitivity of myocardial cells to sympathetic nerve stimulation. In addition, thyroid hormones can also inhibit apoptosis of myocardial cells through PI3K/Akt pathway. Studies showed that levels of thyroid hormones in rats with myocardial infarction was decreased, while supplementing exogenous T3 could inhibit the apoptosis of myocardial cells in myocardial infarction border zones, and increase the left ventricular contractility. This effect was closely related to the activation of Akt pathway stimulated by T3 [30–32]. Therefore, disorder in thyroid hormones may favor septic cardiac dysfunction, and influence prognosis of these patients.

6. Thyroid hormones and lung function

Thyroid hormones are also associated with respiratory function. Studies showed that T3 was required for the synthesis of pulmonary surfactant by type II alveolar cells. Increased plasma T3 levels can augment synthesis of pulmonary surfactant, reduce alveolar surface tension, and increase lung compliance, resulting in improved lung function [19,33,34]. Decreased level of pulmonary surfactant has been found in septic patients, which led to septic pulmonary dysfunction [35]. Further study showed that alveolar surface tension was mainly affected by ratio of apoprotein-A and apoprotein-B, which are members of pulmonary surfactant. In sepsis, level of apoprotein-A mRNA was decreased whereas level of apoprotein-B mRNA was increased. However, T3 treatment could reverse expression level of apoprotein A and B, and thus improve pulmonary dysfunction [36]. Voss et al. found that post-transcriptional modification of apoproteins in the alveolar lumen may reduce the function of surfactant in pathological state [37]. Thyroid hormones can act directly on type II alveolar epithelial cells through their nuclear receptors and affect metabolism of proteins and phospholipids in post-transcriptional levels, and helps to maintain the stability of surfactant monomolecular layer [36,38].

In conclusion, disorder in thyroid hormones may promote development of sepsis and septic organ dysfunctions. Supplementing exogenous thyroid hormones might be useful for septic patients. However, more studies are necessary for clinicians to clarify the timepoint, dosage and clinical outcomes of thyroid hormone supplementation in septic patients.

Footnotes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. NSFC 81270411) and by Program of Wuhan Science and Technology Bureau (No. 2015060101010045).

Conflict of interest

The authors have no conflict of interest to report.

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