As expected, the present study revealed a high prevalence of ESS in hospitalized patients with DK/DKA. Different from previous studies which mainly focused on young patients with T1DM [8–9, 15], most of the patients were middle-aged and elderly patients with T2DM in this research. Moreover, patients with ESS were older in age and had a longer course of diabetes. But the prevalence of ESS was comparable to previous reports.
ESS is considered to be an independent risk factor for the severity of illness and its prognosis (7, 16–18). Previous studies have shown that the reduction of FT3 and FT4 predicted the severity of illness and hospital mortality rates of patients [19]. The changes of thyroid hormone levels in ESS are not associated with primary thyroid disease [16–18, 20]. The reduction of FT3 is an adaptive response to stress during the acute phase response in critical illness [21–22] and the serum level of FT3 could return to normal with treatment and recovery of illness [23]. Shao et al. found that the ESS patients with DKA in children had lower serum FT3, FT4 and TSH, accompanied with worse glucose control [9]. Previous studies demonstrated high prevalence of thyroid dysfunction in DKA patients [19, 24]. These findings were in accordance with our study. In the present research, patients with ESS had lower levels of serum FT3 and FT4, and higher levels of HbA1c. As for the hospitalized outcomes, all the patients got recovered from DK/DKA and thus the mortality rate was 0% in the study. However, much heavier socioeconomic burdens were indicated in the ESS group by a longer hospital stay and higher hospitalization costs. Also, the occurrence of comorbidities including AKI and co-infection were significantly higher in patients with ESS.
The changes in thyroid function can affect renal function directly, as well as make indirect alterations by affecting systemic hemodynamics, metabolism, and cardiac function [25–26]. The relationships between thyroid hormones and renal function have been broadly recognized these years. But most of the evidences came from patients with chronic renal impairment [25–28]. Fewer studies investigated the relationship between thyroid hormones and acute changes of kidney function. Previously, a study reported a high prevalence of ESS (about 70%) in patients with AKI [26]. Recently, several studies showed that ESS at admission increased the risk of AKI after cardiovascular surgeries [29–31]. As known, DK/DKA is a direct imposing factor for AKI. We observed a prevalence of 17.2% for AKI in this research. A previous study in children with DKA reported that there were 64% of patients met the criteria for AKI during their hospitalization [32]. Other studies also documented the high prevalence of AKI in DK/DKA [33, 34]. But few researches explored the the correlation between ESS and AKI in DK/DKA. In our study, we found a higher occurrence of AKI in patients with ESS compared with euthyroid patients. Serum creatinine, eGFR and 24-h urine albumin was significantly associated with serum FT3 level. However, due to the complicated systemic alterations (hemodynamics, metabolism, etc.), the cause-and-effect relationship between changes of thyroid hormones and kidney function in acute diseases has not been well-established based on current evidences. Further studies are needed to elucidate the associations.
In the present study, we assessed parameters reflecting the extent of acidosis, including pH, PaCO2, HCO3− and CO2CP, to evaluate the association between acidosis and the levels of thyroid hormones. We noticed that DK/DKA patients with ESS have higher levels of acidosis. The values of pH and CO2CP were positively associated with both FT3 and FT4 levels. And the prevalence of ESS increased with higher degree of acidosis. Previous studies described similar changes of thyroid hormones in DKA patients [8, 23]. Rashidi et al. pointed out that the lower level of pH in DKA patients, the lower level FT3 [23]. The metabolic acidosis may play important role in the formation of ESS by affecting the thyroid hormone metabolism [35]. Also, CO2CP was manifested as a significant independent risk factor for ESS in DK/DKA patients in our study. Together, these results indicated a connection between acidosis state and the alterations in thyroid hormones in DK/DKA patients.
Serum albumin was suggested to be strongly positively correlated with thyroid hormone (FT3 and FT4) levels in DK/DKA patients in the present study. Albumin is known as a major plasma protein. T3 levels decline in the early stage of ESS, and the decrease of T4 to T3 conversion is related to the reduction in albumin levels [36]. Low albumin level is widely used as a predictor of malnutrition. According to previous researches, malnutrition may be one of the factors affecting thyroid hormones [37, 38]. But in our study, most of the patients were in fine nutritional status. In fact, serum albumin levels may also be influenced by various factors such as liver diseases and changes of intravascular volume [39]. They may decrease as a result of inflammation due to acute or chronic diseases [40]. Therefore, serum albumin has been validated as a measurement of disease severity in the Acute Physiology and Chronic Health Evaluation scoring system [41]. The degradation of albumin level was shown to be an independent predictor of ICU mortality in previous studies [38]. Hypoalbuminemia was also found to be associated with ESS in various kinds of diseases (rheumatoid arthritis [42], COVID-19 infection [43], acute pancreatitis [44], etc). Serum albumin levels were shown to be reduced in ESS pediatric patients with DK/DKA [24]. Besides the aforementioned influencing factors, the deficiency of insulin can also cause a drop in albumin in DK/DKA, since albumin synthesis in hepatocytes depends on sufficient insulin secretion [9, 45]. In the present research, albumin deficiency was also indicated to be an independent risk factor for ESS, and its reduction might present a worse prognosis in DK/DKA patients.
Inflammation is considered as one of the precipitating factors for many pathological circumstances including DK/DKA [46, 47]. It has been reported that DKA is correlated with active systemic inflammatory response, and oxidative stress [48, 49]. Elevations in nonspecific inflammatory cytokines were found to correlate strongly and positively with DK/DKA [50–52]. Previous studies also pointed out that serum levels of thyroid hormones were negatively associated with the serum concentrations of inflammatory cytokines [53]. In the present study, inflammatory indicators, including WBC, neutrophils, hsCRP, N/L ratio, were significantly higher in individuals with ESS, and were negatively associated with FT3. Moreover, elevated WBC and co-infection were risk factors for ESS in DK/DKA. Previous studies have also proposed other factors associated with ESS, including uric acid, serum lipids and other metabolic indicators [54–56]. But in this study, we did not have similar findings.
This study has several limitations. First, it was single-center research with a relatively small number of patients. Second, the cause-and-effect relationship could not be built due to the retrospective nature of the study. Third, follow-up was not done to evaluate the dynamic change of thyroid hormones in ESS patients after recovering of DK/DKA. Therefore, the results need to be cautiously interpreted.
In conclusion, this study demonstrated a high prevalence of ESS in adult DK/DKA patients with elder ages, most of whom were with T2DM. Patients with ESS had inferior clinical and socioeconomic outcomes. Low albumin levels, high WBC counts, poor glycemic control, co-infection, and higher levels of acidosis were risk factors of ESS in DK/DKA patients. Diabetic education, early detection and treatment of DK/DKA is necessary not only for patients with T1DM, but also for patients with T2DM. Early interventions for patients with the identified risk factors for ESS might be helpful to improve hospitalization outcomes.