Clin Exp Nephrol DOI 10.1007/s10157-014-0974-1

REVIEW ARTICLE

An update for the controversies and hypotheses of regulating nonthyroidal illness syndrome in chronic kidney diseases Gaosi Xu • Wenjun Yan • Jingzhen Li

Received: 21 January 2014 / Accepted: 5 April 2014 Ó Japanese Society of Nephrology 2014

Abstract 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 given to verify the NTIS hypothesis in CKD patients.

W. Yan and J. Li have contributed equally to this work. G. Xu (&) Department of Nephrology, Second Affiliated Hospital, Nanchang University, No. 1, Minde Road, Nanchang 330006, People’s Republic of China e-mail: [email protected] W. Yan  J. Li Medical Center of the Graduate School, Nanchang University, Nanchang, China

Keywords Chronic kidney disease  Inflammatory cytokine  Nonthyroidal illness syndrome

Introduction Nonthyroidal illness syndrome (NTIS), which is also named euthyroid sick syndrome (ESS) or low triiodothyronine (T3) syndrome, characterized by decreased serum T3 and thyroxin (T4) levels in critical or noncritical illness, accompanying with increased reverse T3 (rT3) and no significant increase in thyroid-stimulating hormone (TSH). Serum T3 and/or T4 levels are declined in the absence of an obvious thyroid disease [1]. It was reported that approximately one-fourth of endstage renal disease (ESRD) patients present with low serum levels of free T3 (FT3) [2]. Slightly elevated TSH (5–20 IU/ml) was observed in about 20 % of ESRD patients [3]. Among subjects with peritoneal dialysis (PD), the prevalence of hypothyroidism (especially subclinical) and low T3 levels was significantly increased [4]. NTIS was considered as a protective function or an adaptive response to reduce tissue energy consumption in face of critical diseases, or even as a maladaptive one that induces damaging tissue hypothyroid [5]. This is based on the findings that the vast majority of patients recover their thyroid function after the critical diseases [6]. The reason that T4 and free T4 (FT4) are much less frequently decreased in the patients with NTIS is unclear, one of the potential reasons maybe in that the T3 being less tightly bound to thyroxine-binding globulin (TBG) than T4 [7]. NTIS was considered as an adaption of the body to reduce catabolism and make the acute phase response, which is one of the defense mechanisms mainly mediated by cytokines [8].

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NTIS and prognosis in patients with chronic kidney disease (CKD) or other diseases

D1 T4

rT3 D3

Thyroid hormones play a pivotal role in the adaption of metabolic function to stress and critical illness [9]. Total T4 concentrations may be normal or slightly decreased in patients with NTIS, and FT3 is frequently declined as a reflection of reduced conversion of T4–T3 in the periphery [10]. Low concentration of the active form of the thyroid hormone, FT3, is the hallmark of this disorder. The degree of thyroid dysfunction for NTIS in patients CKD matches the severity of kidney damage [11]. Persistently low serum T3 level may finally become a maladaptive response due to its negative prognosis in a variety of severe diseases such as ESRD. Low serum total T3 and FT3 associated with elevated inflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP) predict mortality in patients on dialysis [12]. It can be concluded that inflammation brings about a low FT3 status in ESRD, and that in turn amplifies the effects of inflammation on serum nutritional elements [13]. The low T4 and T3 situation recover gradually after renal transplantation, generally over the first 3–4 months. Post-transplantation thyroid volume and FT3 levels significantly correlated with the graft loss [14]. Low serum T3 levels have been reported to be a strong predictor of mortality in patients with congestive heart failure [15–17], and various acute and chronic diseases [18]. Although the reduction of FT3 and other thyroid hormones in critical illness has been interpreted as an adaptive response to spare calories and protein, in the long term, however, it probably contributes to cause a high-risk condition. For examples, it is an indicator of poor prognosis in intensive care subjects, patients with liver cirrhosis or chronic heart failure, and patients with severe pulmonary diseases [18]. Therefore, a better understanding of the mechanism in NTIS during severe illness is necessary to improve the disease outcome.

Pathophysiological mechanisms of NTIS Deiodinase expression The most important route for thyroid hormone metabolism is through the iodothyronine deiodinases family consisting of three deiodinases, type 1 (D1), 2 (D2) and 3 (D3). D1 is expressed in liver, kidney, thyroid and pituitary and positively regulated by T3, which can deiodinate both the inner and outer ring of T4 and ultimately leading to the formation of 3,30 -diiodothyronine (T2) [19]. D1 and D2 activate T4 through 50 -deiodination (50 -DI) by removing an iodine atom from its outer ring to form T3. D3 inactivates both T3

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D1 D2

D1 D2

T3

D1

T2

D3 Fig. 1 Action of iodothyronine deiodinase

and T4 by removing an iodine atom from their inner rings to generate T2 and rT3, which reaction can also be catalyzed by D1 (Fig. 1). D2 is located in the endoplasmic reticulum and is negatively regulated by thyroid hormone, which deiodinates T4 into the bioactive T3 [20]. Low levels of circulating T3 may alter mitochondrial function, and therefore impairing the use of metabolic substrate and impeding the production of adenosine triphosphate (ATP) [21]. D3 is viewed as the major thyroid hormone-inactivating enzyme because it can catalyze inner-ring deiodination of T4 and T3 exclusively, bringing about the biologically inactive rT3 and reverse T2 (rT2) [22]. Studies showed that D2 is a determinant factor of hypothalamic T3 production [23]. Up-regulation of D2 expression is not specific for the acute phase response, because chronic inflammation in rodents can also induce a short-lived increase of hypothalamic D2 activities [24]. It was speculated that the activation of the nuclear factor-jB (NF-jB) signal pathway may be involved in the hypothalamic inducing of D2, and the reason is that the D2 promoter contains NF-jB-responsive elements [25]. Mechanisms for the changes of thyroid hormone in NTIS Mechanisms for the alternations in thyroid hormone concentrations in NTIS may include the decreased conversion of T4 to T3 in extrathyroidal tissues, decreased pulsatile frequency of TSH secretion resulting from a reduction in thyrotrophic-releasing hormone (TRH) release by hypothalamus, variation in the binding of thyroid hormones to TBG, thyroid hormone transporting and activities of nuclear transport hormone receptors [26]. The alternation of thyroid hormone in CKD The effect of hypothyroidism on renal function is opposite to the effects of hyperthyroidism. When in hypothyroidism

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situation, the renal blood flow is decreased due to the reduction of cardiac output [27], renal response to vasodilators [28], expression of renal vasodilators such as vascular endothelial growth factor and insulin like growth factor-1 [29], the increase of peripheral vascular resistance [30], and intrarenal vasoconstriction [31]. NTIS can mediate the impairment of endothelial function by enhancing endothelial function and norepinephrineinduced vasoconstriction [32]. Additionally, the pathologic changes in glomerular structure such as glomerular basement membrane thickening and mesangial matrix expansion caused by hypothyroidism may also decrease the renal blood flow [33]. Proteinuria, especially in nephrotic syndrome, lead to urinary loss of thyroid hormones binding proteins such as TBG, albumin, prealbumin and transthyretin [34]. TSH is released in response to TRH in CKD patients, indicating pituitary disturbance in uremia [35]. Although there was not significant difference in the serum level of T3 according to the dialysis type, peritoneal dialysis patients presented higher concentration of TSH than that

Fig. 2 The various effects of chronic kidney disease on thyroid profile (adapted from Basu and Mohapatra [37] Interactions between thyroid disorders and kidney disease, Indian J Endocrinol Metab, 2012)

in subjects receiving hemodialysis [36]. The various effects of CKD on thyroid hormone are indicated in Fig. 2 [37]. NTIS was correlated with CKD due to the following reasons. Firstly, chronic metabolic acidosis and protein malnutrition decreased iodothyronine deiodination, which resulted in the reduction in the peripheral conversion of T4 to T3 and its protein binding. Secondly, inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-a inhibited the expression of type 50 DI, which was responsible for the peripheral conversion of T4–T3 [13]. Thirdly, increased serum iodine levels in CKD patients due to the impaired renal function caused a prolonged Wolff-Chaikoff effect [38].

Inflammatory cytokines and NTIS Inflammation is considered as one of the most vital causes of deranged thyroid function related to chronic NTIS [39]. The pro-inflammatory factors in particular interleukins have been reported to downregulate the peripheral conversion of T4–T3 in both experimental and clinical studies [40, 41]. Cytokines were suggested to reduce the binding capability of T3 nuclear receptors [42]. Although the mechanisms involving the role of cytokines on NTIS was poorly understood, the prevailing viewpoint was that NTIS is an acute-phase reaction activated by the cytokine network [43]. Serum IL-6 concentrations were negatively correlated with FT3 and positively with rT3 concentrations [44]. Serum IL-6 is often increased in NTIS, and the serum level of this cytokine is inversely correlated with that of T3 in patients with ESRD [13]. IL-6 may mediate the well-documented inhibitory effects of IL-1 on thyroid cell function [45]. IL-6 decreases hepatocyte thyroxine 50 -DI enzyme expression, and inhibits thyroid function through binding of IL-6 and sIL-6R complex to gp130 [46]. Infusion of recombinant TNF-a in human also produced a significant decrease in serum T3 [47]. Inflammatory cytokines play pivotal roles on thyroid hormone synthesis through an effect on the hypothalamus and pituitary gland. Short-term injection of IL-6 to volunteers led to the suppression of TSH but daily infusion over 42 days resulted only in a modest decrease in T3 [48]. Experimental studies both in human and animals have reported that cytokines, especially IL-1b, IL-6, TNF-a and interferon-c inhibited genes involving in thyroid hormone metabolism, and resulting in partially, but not all features of disease-related NTIS [48–50]. However, cytokines administration can induce the flu-like symptoms. Therefore, it was deduced that the symptoms per se, rather than the cytokines accounted for the NTIS [51].

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Blocking with IL-6, however, failed to induce the euthyroid sick syndrome in animal models [52]. In an experimental IL-6 knock-out mice study, less marked decrease in T3 levels and alternation of liver D1 activity were found after administration of lipopolysaccharide (LPS), which questioned the clinical findings [39].

Oxidative stress and NTIS Oxidative stress due to augmented reactive oxygen species (ROS) or reactive nitrogen species generation is the characteristic of critical diseases associated with NTIS. The patients usually display decreased plasma and intracellular levels of antioxidant scavenging molecules, such as glutathione (GSH), as well as reduced activity of the antioxidant enzymatic system involving ROS detoxification [53]. Adding to the culture median with N-acetyl cysteine (NAC), an antioxidant which increases intracellular GSH concentrations, completely inhibited the preventing effect of IL-6 on D1 and D2-mediated T4 to T3 conversion. It was consistent with the hypothesis that IL-6 inhibits the function of endogenous D1 and D2 by activating cellular ROS, then reducing a GSH-dependent cofactor for D1 and D2 [54]. T3 can reduce cellular oxidative stress and attenuate ROS-mediated damage, along with improving mitochondrial function and energy status in cells [55]. Consistent with clinical findings that serum T3 levels are the first parameter to alter and the last to recover in patients with critical illness, the effect of IL-6 was obvious within a 2-h exposure of the HEK-293 cell, was prevented by the antioxidant NAC, which increases intracellular GSH synthesis [54]. By inducing ROS and specific activation of JAK/ STAT pathways, IL-6 reduces the function D1 and D2 and increases the function of D3, which provides a single explanation for the decreased serum T3 and increased rT3 observed in NTIS with critical illnesses [55]. Whether antioxidants, for example NAC could be beneficial as an adjuvant treatment together with other therapeutic methods in NTIS remains to be appraised.

Should thyroid hormone replacement be recommended in NTIS? The existence of a potential feedback mechanism between thyroid function and immune inflammatory factors in CKD patients indicated that maintenance of normal thyroid function might be important. Reversal of low serum thyroid hormones with physiological replacement of T3 might bring benefits in animal models, and long term L-T3 replacement has been proven to preserve the mitochondria and prevent ischemic cardiac remodeling [56, 57]. In

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patients received coronary artery bypass surgery, T3 infusion improved myocardial function and reduced the need for the amount of vasopressor [58]. A randomized controlled trial (RCT) study reported the effects of T3 replacement in NTIS patients with ischemic or non-ischemic dilated cardiomyopathy and displayed that short term T3 infusion improved the neuroendocrine profile as well as ventricular performance [59]. It was suggested that thyroid hormone replacement was beneficial in NTIS subjects with surgery, heart failure and transplant [60]. It was controversial whether critical ill patients with low serum thyroid hormones should be treated with thyroid hormone replacement [58]. For patients with critical illness, infusion of T4 or T3 restored the serum levels of them, but failed to get clinical benefits [61, 62]. Replacement with 1.5 lg T4/kg promptly returned serum T4 concentration to normal range, but did not normalize T3 concentration over a period of 2–3 weeks [61]. The vast majority of researches in therapy of subjects with NTIS failed to find positive effects of thyroid hormone replacement, although no clear deleterious effects have been found [63, 64]. In a systemic review, T4 treatment increased the mortality 3.3fold in patients with acute renal failure, while serum concentrations of TSH and T3 were not changed [65]. For the sake of the decreased conversion from T4 to T3, replacement with T4 may lead to elevation of rT3 and have little effect on T3 concentrations. In this situation, continued administration of T4 would be harmful. However, it should be expanded to larger studies involving more subjects and longer therapy periods to make the final conclusion.

The significance of NTIS in patients with CKD: how to treat it? Recovering of serum and liver tissue iodothyronine concentration was not achieved by thyroid hormone in substitution dose but instead required several fold of this dose. High-dosage (3–5fold of normal dosage) of thyroid hormone treatment increased serum and tissue iodothyronine concentrations and hepatic D1 activity, as did TRH [66]. Administration of 0.8 lg T3/kg daily to patients with chronic renal failure increased nitrogen excretion from elevated protein catabolism. Therefore, the NTIS could be repaired by increased protein intake [67]. One potential interesting strategy to treat NTIS involves the use of TRb agonists (GC-1), which theoretically allow increase in the metabolic rate and restoration of T3 concentrations without detrimental cardiac acceleration [68, 69]. Clinical researches displayed that decreased TSH releases as well as T3 and/or T4 in severe illness could be recovered by the administration of exogenous TRH in combination with GH-releasing peptide (GHRP)-2 [70,

Clin Exp Nephrol Fig. 3 The hypothesis for the proposed mechanisms of proinflammatory cytokines in the development of NTIS and the proposed treatment selection for NTIS in chronic kidney disease

Progress of Chronic Kidney Disease

Nutrition Supply

Thyroxine, NAC or PH

Negative Regulation

Preventing T3 Decrease Replacement? Negative Feedback Microinflammation

Oxidative Stress (IL1,IL-6,TNF-a)

Inhibition of D1 and D2

Serum IL-1, IL-6 and TNF-a

71]. The neuroendocrine effects coincided with the reduced serum markers of catabolism suggested that hypothalamic down-regulation of the hypothalamus pituitary thyroid (HPT) axis in patients with critical illness is a negative condition amenable to therapy [70]. Recently, two perspective randomized studies indicated that oral intake of sodium bicarbonate not only improved nutritional status, also restored renal function in early and late stage of CKD [72, 73]. The presence of significant increase of T3 after bicarbonate treatment indicated that amelioration of metabolic acidosis might improve peripheral conversion of T4–T3 [74]. In a study of NH4Cl induced metabolic acidosis in healthy volunteers, decreased T3 and T4 were followed by the rise in TSH [75]. Therefore, alkali treatment in CKD patients with metabolic acidosis might be beneficial in recovering T3 and T4 concentrations, ameliorating symptoms of uremia and improving patients’ prognosis. In the proposed feedback system (Fig. 3), the proinflammatory cytokines decrease the peripheral conversion from T4 to T3 by inhibiting of D1 and D2. Declined serum free T3 negatively stimulates the production of the proinflammatory cytokines by depressing the oxidative stress in patients with CKD. NAC or sodium bicarbonate may also negatively regulate the progress of micro-inflammation in CKD. Therefore, large-scale, multi-centered randomized controlled trials should be given to verify the hypothesis. Acknowledgments The research was supported by the National Natural Science Foundation of China (No. 81360122/H0518). No conflict of interests is declared.

Conversion from T4 to T3

Conflict of interest The paper is not under consideration elsewhere.None of the paper’s contents has been previously published.All the authors have read and approved the manuscript.There was not any potential conflict of interest in this paper.

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