The serum levels of anti-TG Ab, anti-TPO Ab, anti-TM Ab, and anti-TR Ab were measured in all 39 RE patients. Mean ± SEM were 6.77 ± 8.70, 8.60 ± 6.05, 3.81 ± 2.71, and 16.77 ± 1.63 IU/mL, respectively. Serum levels of anti-TG Ab, anti-TPO Ab, anti-TM Ab, and anti-TR Ab were normal in each of the 39 individuals.
Of the enrolled 39 patients, 4 (10.3%) patients were euthyroid with normal FT3, FT4, and TSH levels. Thirty-three (84.6%) patients were diagnosed with LT3S, which was defined as a low serum FT3 level without an elevated TSH level. Among them, 1 patient was with concomitant low FT4 level, and 6 patients were with concomitant low TSH level. Two (5.1%) patients were diagnosed with hypothyroidism because of a low FT3 and increased TSH level (Figure 2).
We further compared the differences between euthyroid and LT3S groups in RE patients. Table 2 showed the demographics and clinical variables between these 2 groups. Age, sex distribution, BMI, APACHEII score, history of hypertension and diabetes, radiotherapy parameters, Hb, WBC, and CRP were similar between euthyroid and LT3S patients. In contrast, TP (71.7 ± 5.7 vs 63.2 ± 9.6 g/L, P = 0.04) and ALB (46.0 ± 4.6 vs 38.7 ± 5.3 g/L, P = 0.01) were significantly lower in LT3S group compared with those in euthyroid group, suggesting a worse nutritional condition in patients with LT3S. Meanwhile, FT3 (4.63 ± 0.73 vs 3.01 ± 0.61 pmol/L, P = 0.00), TT3 (1.64 ± 0.14 vs 0.96 ± 0.30 nmol/L, P = 0.00), TSH (2.10 ± 1.43 vs 1.08 ± 0.90 mIU/L, P = 0.03), sTSHI (−0.89 ± 2.11 vs −2.39 ± 1.33, P = 0.03), and GD (19.74 ± 4.19 vs 12.55 ± 4.32 nmol/L, P = 0.01) were significantly lower in LT3S group, whereas other thyroid hemostasis parameters were similar between these 2 groups (Table 2). The decreased levels of sTSHI (−2.39) and GD (12.55 nmol/L) presumed a downregulation of pituitary-thyrotroph function and hypodeiodination in LT3S group, which meant a hypodeiodination condition and a potential pituitary-thyrotroph dysfunction may play a role in the pathophysiology of LT3S in RE.
To further investigate the correlation between clinical variables and thyroid parameters, we performed univariate and multivariate linear regression analysis. Clinical variables included age, sex distribution, BMI, APACHEII score, WBC counts, Hb, CRP, TP, ALB, and radiotherapy parameters. TP (β = 0.331, 95% CI = 0.001–0.055, P = 0.046) and ALB (β = 0.441, 95% CI = 0.019–0.106, P = 0.006) emerged as potential predictors, which meant both TP and ALB were with a close relationship to serum concentration of FT3. Then we performed a multiple linear regression model to further investigate factors that were actually associated with FT3 level. In multivariate analysis, low serum ALB concentration (β = 0.694, 95% CI = 0.007–0.190, P = 0.037) was the only significant predictor of LT3S (Table 3).
Clinical outcomes, including presentation of diarrhea and obstruction, days of hospitalization, and percentages of operation were further analyzed. As shown in Table 4, the patients with LT3S displayed a statistically longer stay of hospitalization compared with that in euthyroid group (48.25 ± 23.29 days in LT3S vs 26.75 ± 10.56 days in euthyroid, P = 0.036). Differences of presentation of diarrhea (81.8% in LT3S vs 50.0% in euthyroid, P = 0.923) and obstruction (60.6% in LT3S vs 50.0% in euthyroid, P = 0.683), and percentages of operation (78.8% in LT3S vs 50.0% in euthyroid, P = 0.205) between LT3S and euthyroid groups were not confirmed (Table 4). However, even the differences were not significant enough to reach statistical standard, the present study still implied a more severe presentation of diarrhea (diarrhea >5 times a day, 15.2% in LT3S vs 0.0% in euthyroid, respectively), greater percentages of obstruction, and higher probabilities of operation in LT3S individuals.
This was the first investigation to evaluate the clinical correlation between RE and LT3S, investigate the prevalence of LT3S in RE, and explore the pathogenesis of LT3S. In the present study, we prospectively collected 39 patients in our center. We demonstrated that the incidence of LT3S in RE was 84.6%, which was observed higher than the incidence of other thyroid disorders, including hypothyroidism (5.1%). Of the 33 LT3S patients, 6 patients were with concomitant low TSH concentrations, thereby indicating changes in the hypothalamic-pituitary regulation; 1 patient was with concomitant low FT4 concentration, which may also be due to an impaired hypothalamic or pituitary regulation.22 Despite these changes, serum concentrations of anti-TG Ab, anti-TPO Ab, anti-TM Ab, and anti-TR Ab were normal in all patients enrolled in our study, which conformed there was no autoimmune thyroid disease in all the 39 individuals.
In several illnesses, LT3S has been described as decreased T3 with a normal or low concentration of T4 and a normal or low concentration of TSH. Previous studies reported that about 70% of patients hospitalized with various illnesses were affected by LT3S.23 Although this pattern has been clinically described for more than 30 years, it still remains controversial what is the likely mechanism behind these changes and whether the presence of LT3S belongs to a result of a maladaptive or a protective process.24,25 Multiple factors such as dysfunction of hypothalamic-pituitary-thyroid axis and altered peripheral thyroid hormone metabolism are demonstrated to be essential mechanisms in the pathogenesis of LT3S.26 To the best of our knowledge, there is no study reporting occurrence rate of LT3S in RE in literature and there is a lack of study focusing on the correlation of LT3S and RE. However, our study displayed LT3S occurred frequently with a prevalence of (84.6%) in RE, which was higher than previously reported in hospitalized cardiac patients (30%) and in acutely ill elderly patients (32%),27,28 reminding clinical physicians to be aware of the possibility of LT3S occurrence in RE.
In this study, the age and sex distribution, the BMI and APACHE II score, the presence of diabetes and hypertension, and the radiotherapy parameters had no influence on serum concentrations of T3, T4, and TSH. Low serum concentrations of TP and ALB were recognized as risk factors for LT3S in RE in current study, suggesting a worse nutritional status in patients with LT3S. Patients with high serum concentrations of TP and ALB were less likely to have LT3S. This emphasizes the critical importance of routine surveillance of serum TP and ALB concentrations in RE patients, which may be helpful for clinical physicians to identify the occurrence of LT3S in RE. Of note, we did not evaluate the efficacy of ALB supplementation for improving clinical variables and prognosis, and the effect of ALB supplementation on thyroid hormone metabolism in RE patients with LT3S. Larger prospective, multicenter studies were expected to explore these issues.
Furthermore, we tried to explore the pathogenesis of LT3S in RE. LT3S was generally characterized by 3 components, which could occur solely or in combination:
- Impaired protein binding of thyroid hormones, thus the ratios of TT3/FT3 and TT4/FT4 were measured in our study cohort to reveal the binding condition
- Central hypothyroidism (transient thyrotropic insufficiency), accordingly parameters of sTSHI and TSHI were measured to assess the pituitary thyrothroph function
- Reduced formation of T3 with concomitantly increased conversion of rT3, thus the parameter of GD was calculated to assess the deiodination status21
In addition, we calculated the parameter of GT to evaluate the thyroid function. Our results demonstrated a reduced GD level in LT3S group compared with euthyroid group. Combining with the consideration of the decreased concentration of FT3, we speculated that a decreased deiodination condition may be partially responsible for the occurrence of LT3S in patients with RE. In addition, another key finding in this study was a lower sTSHI in LT3S group, suggesting a potential pituitary-thyrotroph dysfunction may also play a role in the pathogenesis of LT3S in RE patients. However, since the parameters of TT3/FT3 and TT4/FT4 between these 2 groups were not significant enough to reach statistical standard, larger multicenter studies were expected to further explore the pathogenesis of LT3S in RE.
Meanwhile, our results showed that patients in the LT3S group displayed longer stays in hospital compared with the euthyroid group. Patients in our cohort with LT3S also had a more severe presentation of diarrhea, greater percentages of obstruction, and higher probabilities of operation than those with normal thyroid function, although the differences were not statistically significant. We speculated that the limited sample size of the present study might be the primary factor in the prevention of discovery, and believed that larger multicenter studies would be a great advance for exploring the clinical variables and prognosis between euthyroid and LT3S groups. Our results were consistent with previous published studies of critical and chronic illnesses.8,27,28
Treatment of patients affected by LT3S with thyroid hormones has been controversially discussed, and there were only a few studies in humans with small numbers available so far.29–32 Treatment with T3 has been investigated in coronary artery bypass surgery31,32 and in burn patients,30 but its clinical benefit has not been repeatedly shown yet. For example, in patients undergoing heart surgery32,33 or in patients with heart failure,34 thyroid hormone replacement therapy was safe and improved hemodynamic function; however, the benefit with respect to mortality remains less clear. Others have reported that thyroid hormone replacement therapy did not improve clinical outcomes in patients with burn injuries30 and in intensive care unit patients.29 Another possible treatment includes the substitution of T4, which restored serum T4 concentrations but reduced TSH concentrations and failed to show a clinically beneficial effect.29
We are aware that some limitations of this study merit consideration. First, as a single-center study, a potential selection bias might limit the extrapolation of our results. However, all measurements were performed within 24 hours of admission, which makes our study homogeneous. Second, as only 39 RE patients were enrolled in our study, the sample size might be a little small to detect the real diversity of duration of hospitalization and possibilities of operation between LT3S and euthyroid groups. In addition, we did not have the opportunity to measure levels of proinflammatory cytokines, which might have given slightly different results of our study. Also, whether replacing thyroid hormones and raising FT3 into the normal range could help to improve the outcomes of RE patients in LT3S group is unknown.
In summary, LT3S is a common complication in RE patients and is independently associated with increased risk for worse nutritional status and clinical outcomes. The present findings also indicate that a potential pituitary-thyrotroph dysfunction and a hypodeiodination condition may contribute to the pathogenesis of LT3S in RE. Furthermore, TP and ALB are recognized as protective and distinguishing factors of LT3S in RE. However, due to the limitations of this study, further study will be needed to clarify whether LT3S in RE is a useful compensatory mechanism to counteract excessive catabolism or an unfavorable adaptation, and whether it is necessary to treat LT3S with hormone replacement therapy in RE patients.
The authors thank the grant from the National Natural Science Foundation of China (no.81270945).
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