Introduction

Thyroid hormones (TH) are endocrine hormones secreted by the thyroid gland with important physiological functions, and have always been a mandatory indicators for evaluating thyroid function. Nonthyroidal illness syndrome (NTIS) refers to the changes in thyroid hormones caused by non-thyroid systemic or wasting diseases, while the thyroid has no organic changes, also known as normal thyroid sick syndrome (Euthyroid sick syndrome, ESS)1,2. Low triiodothyronine (T3) syndrome, low thyroxine (T4) syndrome, or high T4 syndrome are common clinically. At this time, serum thyroid-stimulating hormone (TSH) levels can be normal, decreased, or slightly elevated3,4.

The alteration of TH level may be related to the body's health status, disease development and outcome. Animal research have illustrated serum concentrations of T3, T4, FT4 and TSH in cats complicated with NTIS decreased progressively with the aggravation of the disease, and the lower the T4 or TSH level, the higher the mortality rate5. Padhi et al.6 reported patients with severe sepsis often have NTIS, and the prognoses of both T3 and T4 reduction were worse than that of T3 alone. Concurrently, some scholars have found patients with liver failure often developed NTIS, and the FT3 value can better assess the mortality of patients with liver failure7. Recent studies have shown that patients with COVID-19 presenting with NTIS not only had low FT3, but also low FT4 and TSH, and low FT4 and TSH concentrations were closely associated with the mortality of COVID-19. In addition, low TSH levels were also independent risk factors for death from COVID-198. Therefore, it followed that NTIS was associated with either infection or organ dysfunction, and low TH and TSH levels were closely related to patient prognosis. The purpose of this study was to analyze the case data and thyroid function of emergency inpatients, investigate the prevalence of NTIS in hospitalized patients in emergency state with infection and organ injury, and analyze the correlation between thyroid function and disease conditions, so as to clarify the importance of thyroid hormone detection in emergency department.

Material and methods

Subjects

The case data and thyroid hormone function of 175 inpatients in emergency department of our hospital from January 2021 to June 2021 were retrospectively analyzed. According to clinical diagnoses, they were divided into three categories, namely non-infection group, infection group and impaired organ function group (mainly refers to the primary three major organ function impairments such as cerebral stroke, renal insufficiency and cardiac insufficiency, etc.). The infection group was divided into three groups: sepsis group (sepsis; septic shock; bilateral blood culture positive; all of the above were in line with the 2016 sepsis 3.0 diagnostic criteria); lung infection group (including pneumonia and lung infection) and local infection group (such as liver abscess; lung abscess; erysipelas or pancreatitis), a total of five groups. Inclusion criteria: emergency inpatients who were not thyroid per se, but had non-thyroidal disorders with abnormal TH metabolism mainly due to primary acute or chronic diseases, with reduced serum FT3 or T3, reduced FT4 or T4 and with complete thyroid function tests and clinical data were included in the NTIS group. Conversely, those with normal thyroid function and complete data were included in the non-NTIS group. Exclusion criteria: pregnant women, trauma, abdominal pain, malignant tumors, endocrine disorders such as hyper- or hypothyroidism; recent administration of drugs that affect thyroid secretion or metabolism. According to patients' conditions at the time of discharge, the disease outcomes were divided into two categories: improvement and death. This study (Approval No. 2023-LWKY-043) was reviewed and approved by the Ethics Committee of the Affiliated Hospital of Integrative Medicine of Nanjing University of Traditional Chinese Medicine.

Measurement

The levels of thyroid hormones T3, T4, FT3, FT4 and TSH in serum were detected by chemiluminescence with Cobas e602 instrument. All quality control was under control. The testing and calibration reagents were the auxiliary reagents of the instrument, and the quality control products were provided by Bio-Rad Company in the United States. Reference ranges of thyroid function and other main test indicators were as follows: T3: 1.30–3.10 nmol/L; T4: 66.00–181.00 nmol/L; FT3: 3.10–6.80 pmol/L; FT4: 12.00–22.00 pmol/L; TSH: 0.27–4.20 IU/mL; ALb: 40.0–55.0 g/L; CRP: 0–4.00 mg/L; PLT: 125.0–350.0 × 109/L; D-Dimer: 0.00–0.50 mg/mL; IL-6: 0.00–7.00 pg/mL; Fer: 30.00–400.00 ng/mL.

Statistical analysis

Enter data in Excel form, GraphPad Prism6.0 software (GraphPad Software, CA, USA) to make graphs, and use SPSS17.0 software (SPSS inc. Chicago, USA) for statistical analysis. The measurement data of normal distribution are expressed as mean ± standard deviation, and performed by One-way analysis of variance (ANOVA) followed by Tukey’s post-hoc test was used for multiple comparisons. Median and interquartile range M (P25–P75) were used for measurement data that did not confirm to normal distribution. Kruskal–Wallis H test of non-parametric test was for inter-comparison. The count data were expressed as the number of cases (%), and the rates were compared by chi-square (χ2) test; the correlation between TH and other laboratory indicators was analyzed by Spearman's correlation analysis. ROC curves were plotted and AUC values were calculated to analyze the values of TH levels in predicting the risk of death in emergency inpatients; AUC > 0.70 indicates good predictive value, and 0.5 ~ 0.7 indicates average predictive performance. P < 0.05 was considered statistically significant.

Ethics approval

For experiments involving human participants (including the use of blood samples), the informed consent was obtained from all subjects or their legal guardians. This study was reviewed and approved by the Ethics Committee of the Affiliated Hospital of Integrative Medicine of Nanjing University of Traditional Chinese Medicine (Approval No. 2023-LWKY-043). It was conducted according to the guidelines of the Declaration of Helsinki.

Results

General characteristics of case data

There were 175 inpatients in the emergency ward, aged 15–85 years old, with an average age of 66.12 ± 16.23 years. Among them, 109 cases were combined with NTIS and 66 cases were non-NTIS. The number of cases in the NTIS group accounted for 62.29%. There was no significant difference in the sex ratio between NTIS, non-NTIS and the overall group (P > 0.05), but the age of non-NTIS group was lower than that of the NTIS group and the overall group. Further analysis found the serum levels of T3, T4, FT3 and FT4 in NTIS group were significantly lower than those in the non-NTIS group and overall group (P < 0.05; P < 0.01), but there was no significant difference in TSH. The levels of hematological indicators C-reactive protein (CRP), platelets (PLT), D-Dimer, interleukin (IL)-6 and ferritin (Fer) in the NTIS group were higher than those in other groups, except for PLT (P < 0.05; P < 0.01), while albumin (ALb) was significantly lower than that of the other two groups (P < 0.05). The mortality of NTIS group was higher than non-NTIS group and total group (P < 0.05). The basic characteristics and other hematological indicators of the subjects are shown in Table 1 and Fig. 1.

Table 1 Baseline characteristics and thyroid function of the study groups.
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Figure 1
figure 1

Hematological characteristics and thyroid function among total group, non-NTIS group and NTIS group. *P < 0.05 vs total group; #P < 0.05, ##P < 0.01 vs non-NTIS group.

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Incidence of hypothyroidism

Analysis of the 5 hormone levels in 175 inpatients found the incidence of low triiodothyronidemia was the highest (56.00%), followed by low free triiodothyronidemia (46.86%), and the incidence of low TSH was the lowest (9.71%). The incidence of low triiodothyronidemia and low free triiodothyronidemia were higher, which was significantly different from other groups (P < 0.01); the low ratios of T4 and FT4 levels were low, 12.57% and 11.43%, respectively, and T4 had statistical difference compared with other groups (P < 0.05; P < 0.01). As shown in Table 2.

Table 2 Ratio of low thyroid hormone levels.
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The rate of concurrent NTIS in each clinical diagnosis group

According to the clinical diagnoses of 175 inpatients, they were divided into 5 groups, namely non-infection group, local infection group, lung infection group, impaired organ function group and sepsis group (Fig. 2). See Table 3 for details. Analysis of NTIS concomitant in each diagnostic group showed the sepsis group had the highest proportion of NTIS (83.33%), followed by the impaired organ function group (78.12%); The incidence of NTIS in lung infection group and local infection group decreased gradually (62.68% and 34.78%, respectively), and the lowest in the non-infected group (23.52%). The incidence of NTIS in the sepsis group, impaired organ function group, lung infection group and local infection group was statistically different from that in the non-infection group (P < 0.05, P < 0.01); Compared with local infection group and non-infection group, the sepsis group, impaired organ function group and lung infection group had significant differences (P < 0.05, P < 0.01); there was no statistical difference between the sepsis group and the impaired organ function group. See Table 3 and Fig. 3.

Figure 2
figure 2

Details of the clinical diagnoses groups (A) Comprehensive sum of each clinical diagnosis group, (B) Sepsis group, (C) Impaired organ function group, (D) Lung infection group, (E) Local infection group, (F) Non-infection group.

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Table 3 The incidence of NTIS combined in each clinical diagnosis groups.
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Figure 3
figure 3

The numbers and rate of combined NTIS in each clinical diagnosis group. #P < 0.05, ##P < 0.01 vs non-infected group; *P < 0.05, **P < 0.01 vs local infected group and non-infected group.

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The low value rate of TH in each clinical diagnosis group

The incidence of low TH values in each clinical diagnosis group was the highest in T3, 72.22% in sepsis group, and 68.75% in organ failure group; followed by FT3, 66.67% in sepsis group, and 62.50% in organ failure group. Which were statistically different from those in local infection group and non-infection group (P < 0.05; P < 0.01), T3 was the most sensitive indicator, followed by FT3. T4 was the highest in the impaired organ function group (40.62%), 22.22% in the sepsis group, followed by FT4 in the impaired organ function group (28.13%), and 11.11% in the sepsis group. It can be seen that T4 was an indicator of severe diseases, followed by FT4 (Table 4).

Table 4 The low value rate of TH in each clinical diagnosis group.
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TH levels in each clinical diagnosis group

Except for FT4, the TH levels in sepsis group, impaired organ function group, lung infection group and local infection group were lower than those in non-infection group (P < 0.05; P < 0.01); The levels of T3 and FT3 in sepsis group and impaired organ function group were significantly lower than those in other groups (P < 0.05; P < 0.01), the lowest FT3 level was found in the sepsis group, and the lowest T4 level was found in the impaired organ function group, with statistical difference compared with other groups (P < 0.05; P < 0.01), and there was no statistical difference in FT4 and TSH levels among groups. See Table 5 for details.

Table 5 Comparison of TH levels in each group.
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Correlation between thyroid hormone levels and other blood indicators

Correlation analysis of TH levels and blood inflammation indicators or nutritional indicators indicated that, except for T4 and PLT, T3/T4/FT3 were strongly related to the above indicators (Alb; CRP; PLT; D-Dimer; IL-6; Fer). Further analysis revealed that T3/T4/FT3 were positively correlated with Alb and PLT, and inversely correlated with CRP, D-Dimer, IL-6 and Fer. FT4 was basically unrelated to the above indexes; TSH was almost not related to other indicators except for negative correlation with CRP and IL-6. The details are shown in Fig. 4 and Table 6.

Figure 4
figure 4

Scatter plot of the correlation between TH levels and inflammation or nutritional indicators. (A–F) Scatter plot of correlation between Alb/CRP/PLT/D-Dimer/IL-6/Fer and TH respectively.

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Table 6 Correlation analysis of TH levels and inflammatory indicators or nutritional indexes.
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TH predicts the risk of death

The ROC curves for serum thyroid hormones to predict the risk of death occurring in emergency hospitalized patients showed the AUC and 95% Confidence Interval (CI) of T3, T4, FT3, FT4 and TSH were [(0.750, 0.673–0.828, P < 0.001); (0.684, 0.595–0.774, P < 0.001), (0.723, 0.640–0.806, P < 0.001), (0.614, 0.496–0.732, P = 0.034), (0.629, 0.529–0.730, P = 0.016)] respectively. For predicting the mortality risk in patients, T3 has a good predictive effect, followed by FT3, T4 was slightly lower, FT4 and TSH had almost no predictive function. See Fig. 5.

Figure 5
figure 5

ROC curves of thyroid hormones predicting death risk in emergency inpatients.

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Discussion

Thyroid hormones are involved in human growth and development, metabolism and balance, and are also one of the signs reflecting the body health. Thyroid dysfunction, especially changes in T3 levels, may occur in emergency state or severe cases. The results of this study showed that the incidence of NTIS among inpatients in emergency ward was 62.29%, which was also supported by the results of the same type of study9. In this investigation, the population in emergency ward was mainly critical patients, mostly middle-aged and elderly, with a high incidence of NTIS. We also found that patients with sepsis and impaired organ function had the highest incidence of NTIS, followed by pulmonary infection and local infection, and correspondingly decreased T3, T4 and FT3 levels, but the reduction was not significant in the non-infection group, and the influence of each diagnosis group on FT4 and TSH differed less. It can be seen that systemic infection and organ failure have a greater impact on TH levels, indicating the severity of the patients' conditions.

This study found patients with NTIS not only had the most significant reductions in T3 and FT3 levels, but also had the highest prevalence of hypoemia of T3 or/and FT3 (56.0% and 46.86%, respectively), followed by hypoemia T4 (17.14%) and FT4 (11.43%), and TSH was the lowest. Accumulating evidences have shown the decrease of T3/FT3, T4/FT4 and TSH may occur simultaneously in acute and chronic severe patients10. Guo et al.11 revealed that the reduction of FT3 had a certain value in evaluating the prognosis of common type progressing to severe type. T4 decline was more common in severe patients. For example, the T4 level of patients with damaged organ function in this investigation was the lowest, followed by sepsis patients with systemic infections. This is because T3 can be transformed from T4, but T4 (FT4), regulated by TSH, is all secreted by thyroid gland. When the condition is critical, on the one hand, the secretion level of TSH is down-regulated, and on the other hand, the secretion of strong pro-inflammatory factors such as IL-6 and TNF-α blocks the effect of TSH on the thyroid gland, and together, the synthesis and secretion of T4 and FT4 are reduced. This research also manifested that patients with concurrent NTIS had worse outcomes and higher mortality. Above results indicated the prognosis of patients with NTIS was poor. the decrease of T3/FT3 levels were the most sensitive parameter for the occurrence and development of diseases in hospitalized patients, and T4 may be an important indicator for judging the severity of diseases.

The correlation analysis between TH and other blood indicators in this study indicated TH levels were positively correlated with nutritional indicator ALb, while negatively correlated with inflammatory-related indicators such as CRP, PLT, D-Dimer, IL-6 and Fer, especially T3/T4/FT3, which was also consistent with the occurrence mechanism of NTIS. Sepsis was also a pan-endocrine disease, which was a life-threatening organ dysfunction caused by the imbalance of the host response to infection. One of the elements of the host response disorder was the dysfunction of the hormone axis, especially hypothalamic–pituitary–thyroid (H–P–T) axis, which led to disorders of the endocrine system in patients with sepsis12. The inflammatory factors released during the disease were considered to be the main determinants of the development of NTIS, as these factors affect various genes involved in TH metabolism13. Under hyperinflammatory conditions, pro-inflammatory factors such as IL-6 and TNF-α not only act on H–P–T, inhibit the synthesis and secretion of TH, but also prevent the expression of TH receptors TRα and TRβ, further aggravating the occurrence of NTIS6,14. We know platelets originally have functions such as blood clotting and maintaining the integrity of vessel walls, but a growing number of studies have revealed platelets can also play a role as an inflammatory immune cells and closely related to many diseases such as tumors, cardiovascular diseases, autoimmune diseases or sepsis15; d-Dimer is associated with thrombosis and secondary hyperfibrinolysis. Recently, it has been found inflammatory factors released in disease states or infectious pathogens can damage the vascular endothelium and activate blood coagulation, thereby secondary hyperfibrinolysis and increased D-Dimer16; Fer and CRP are both acute phase reactive proteins, which rise sharply during disease or infection. The elevated Fer blocked iron required for pathogen growth and prevented the production of free radicals, thereby mediating immune regulation to enhance host immune defense function17; CRP is induced by IL-6 or other inflammatory factors in the liver18. which is why d-Dimer, platelets, Fer, and CRP are elevated in NTIS. This study also manifested TH levels were closely related to the prognoses of patients, especially the reduction of T3 level had the highest correlation with the risk of death, followed by FT3, and T3 was the most valuable indicator to evaluate the prognosis.

It is still controversial whether thyroxine therapy is necessary for NTIS. It has been reported oral low-dose TH can prevent the occurrence of NTIS and improve the damage of the original diseases19,20. However, long-term studies believe that NTIS is a self-regulation of the body in various acute and chronic disease states to reduce energy consumption and maintain basic metabolism. It is an adaptive response of the body to diseases, so TH is not required. For severe cases, the reduction of TH levels can also be regarded as a beneficial protective mechanism of the body, conducive to the alleviation of the disease.

Collectively, this study suggested T3 is the most sensitive indicator for the diagnosis of inpatients and the most valuable indicator for evaluating prognosis. When diseases progressed to severer, T4 decreased. These shows that for critically illnesses, attention should be paid to monitoring T3 and T4 levels. If patients complicated with NTIS can be detected in time, intervention measures can be taken as soon as possible, and active symptomatic treatment can be taken to improve the prognosis and reduce the fatality rate.