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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 12 6460-6465
Copyright © 2005 by The Endocrine Society

Increased Thyroxine Sulfate Levels in Critically Ill Patients as a Result of a Decreased Hepatic Type I Deiodinase Activity

Robin P. Peeters, Monique H. A. Kester, Pieter J. Wouters, Ellen Kaptein, Hans van Toor, Theo J. Visser and Greet Van den Berghe

Department of Internal Medicine (R.P.P., M.H.A.K., E.K., H.v.T., T.J.V.), Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands; and Department of Intensive Care Medicine (P.J.W., G.V.d.B.), Catholic University of Leuven, B-3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Greet Van den Berghe, M.D., Ph.D., Department of Intensive Care Medicine, Catholic University of Leuven, B-3000 Leuven, Belgium. E-mail: greta.vandenberghe{at}med.kuleuven.ac.be.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Introduction: Marked changes in peripheral thyroid hormone metabolism occur in critical illness, resulting in low serum T3 and high rT3 levels. In this study, we investigated whether T4S levels are increased in patients who died after intensive care and whether T4S levels are correlated with liver type I deiodinase (D1) or sulfotransferase (SULT) activity.

Methods: A total of 64 blood samples and 65 liver biopsies were obtained within minutes after death from 79 intensive care patients, randomized for intensive or conventional insulin treatment. Serum T4S and the activities of hepatic D1 and 3,3'-diiodothyronine (T2)-SULT and estrogen-SULT were determined.

Results: No differences in T4S or hepatic SULT activities were found between patients treated with intensive or with conventional insulin therapy. T4S levels were significantly elevated compared with healthy references. Furthermore, hepatic D1, but not SULT activity, showed a strong correlation with serum T4S (R = –0.53; P < 0.001) and T4S/T4 ratio (R = –0.62; P < 0.001). Cause of death was significantly correlated with hepatic T2- and estrogen-SULT activities (P < 0.01), with SULT activities being highest in the patients who died of severe brain damage and lowest in the patients who died of a cardiovascular collapse. A longer period of intensive care was associated with higher levels of T4S (P = 0.005), and high levels of bilirubin were associated with low T2-SULT (P = 0.04) activities and high levels of T4S (P < 0.001).

Conclusion: Serum T4S levels were clearly elevated compared with healthy references, and the decreased deiodination by liver D1 during critical illness appears to play a role in this increase in serum T4S levels.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
DURING CRITICAL ILLNESS, pronounced alterations in the hypothalamus-pituitary-thyroid axis occur without any evidence for thyroid disease (1, 2, 3, 4). Decreased plasma T3 and increased plasma rT3 levels are the most common changes, and the magnitude of these changes is related to the severity of the disease (1, 2, 5). This combination of decreased serum T3 and increased serum rT3 levels indicates major changes in the peripheral metabolism of thyroid hormone, which is mediated importantly by the three iodothyronine deiodinases D1, D2, and D3 (see Refs.5 and 6 for reviews). Reduced activity of D1 and increased activity of D3 have been shown in postmortem liver and skeletal muscle tissues of nonthyroidal illness patients (1, 7).

The role of sulfation in thyroid hormone metabolism is fascinating. Sulfated iodothyronines do not bind to the thyroid hormone receptors, and sulfation mediates the rapid and irreversible degradation of iodothyronines by D1 (8). Therefore, the concentrations of sulfated iodothyronines in serum are normally low (9, 10, 11, 12). Inner ring deiodination (inactivation) of T4 and T3 by D1 is markedly facilitated after sulfation, whereas outer ring deiodination of T4 is blocked after sulfation (13, 14, 15). D2 and D3 are incapable of catalyzing the deiodination of sulfated iodothyronines (15).

Iodothyronine sulfation is catalyzed by cytosolic sulfotransferases (SULTs) using 3'-phosphoadenosine-5'-phosphosulfate (PAPS) as the sulfate donor (16, 17, 18). The SULTs show overlapping substrate specificity. In humans, they can be subdivided into different families, SULT1, SULT2, SULT4, and SULT6 (19, 20). It has been shown that all members of the human SULT1 family, i.e. hSULT1A1, -1A2, -1A3, -1B1, -1C2, -1C4, and -1E1, catalyze the sulfation of iodothyronines (21, 22, 23, 24). hSULT1A1–3, -1B1, and -1C4 and also native enzymes in liver have a substrate preference for 3,3'-diiodothyronine (T2), which is catalyzed much faster than T3 and rT3, whereas T4 sulfation is negligible (20, 23, 24). hSULT1E1 equally prefers T2 and rT3 over T3 and T4 but is the only known SULT so far having significant T4-SULT activity (23).

Elevated T4S levels and T3S/T3 ratios have been reported in nonthyroidal illness patients, and T4S levels are increased in preterm infants (11, 12, 25, 26). In this study, we investigated whether T4S levels are increased in patients who died in the intensive care unit (ICU) and whether T4S levels are correlated with liver D1 or SULT activity. Furthermore, we investigated whether T4S levels or SULT activities were regulated by different parameters of disease during critical illness. All patients in this study had been randomized for insulin treatment as part of a large clinical trial that was published in detail elsewhere (27).


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

This study was part of a large randomized controlled study on intensive insulin treatment in ICU patients (n = 1548), of which the major clinical outcomes have been published in detail elsewhere (27). All mechanically ventilated patients were eligible for inclusion in this trial after informed consent from the closest family member. On admission, patients were randomly assigned to either strict normalization of blood glucose (80–110 mg/dl) with intensive insulin therapy or the conventional approach, in which insulin infusion is initiated only when blood glucose exceeds 215 mg/dl, to maintain blood glucose levels between 180 and 200 mg/dl. The study protocol has been approved by the Ethical Review Board of the University of Leuven School of Medicine.

A total of 79 patients were included in the current study. All patients included had died in the ICU, and the cause of death was determined both clinically by the attending ICU physician and by postmortem examination. The pathologist was unaware of insulin treatment allocation. Relevant patients’ characteristics are summarized in Table 1Go.


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  		TABLE 1. Descriptive statistics of the population investigated in this study

 
Blood samples were obtained from 64 patients and liver biopsies from 65 patients within minutes after death. From 50 patients, both serum and liver samples were available. From an additional 14 patients, only a liver sample was available, and from 15 other patients, only serum was available. The total number of patients in this study was therefore 79. All patients had been randomized for conventional or intensive insulin treatment (27). Thirty-one patients had been treated with thyroid hormone during the course of their critical illness. Treatment was initiated when they had a serum T4 concentration less than 50 nmol/liter in the face of a normal T4-binding globulin and concomitantly clinical symptoms of hypothyroidism (7). In these cases, thyroid hormone treatment consisted of an iv bolus of 150 µg T4 daily plus 0.6 µg T3 per kg body weight per 24 h as a continuous iv infusion.

Serum analyses

Serum total T4, total T3, and TSH were measured by chemoluminescence assays (Vitros ECi Immunodiagnostic System; Ortho-Clinical Diagnostics, Amersham, Little Chalfont, UK). rT3 was measured by RIA as previously described (28). T4S was prepared by the method of Eelkman Rooda et al. (29). Serum T4S was measured using a specific antibody, as described previously (30). Within-assay coefficients of variation amounted to 4% for TSH, 2% for T4, 2% for T3, 3–4% for rT3, and 6–17% for T4S. Normal values (mean ± 2 SD) for T4S were determined in 172 healthy individuals.

D1 and SULT activities

Human liver and muscle samples were homogenized on ice in 10 vol of PE buffer (0.1 M phosphate, 2 mM EDTA, pH 7.2) using a Polytron (Kinematica AG, Lucerne, Switzerland). Homogenates were snap-frozen in aliquots and stored at –80 C until further analysis. Protein concentration was measured with the Bio-Rad (Veenendaal, The Netherlands) protein assay using BSA as the standard following the manufacturer’s instructions.

Liver D1 activities were determined as described earlier (31) by duplicate incubations of homogenates (10 µg protein) for 30 min at 37 C with 0.1 µM [3',5'-125I]rT3 (100,000 cpm) in a final volume of 0.1 ml PE buffer with 10 mM dithiothreitol). Reactions were stopped by addition of 0.1 ml 5% (wt/vol) BSA in water on ice. The protein-bound iodothyronines were precipitated by addition of 0.5 ml ice-cold 10% (wt/vol) trichloroacetic acid in water. After centrifugation, 125I– was isolated from the supernatant by chromatography on Sephadex LH-20 minicolumns (32).

T2-SULT activity was analyzed by incubation of 0.1 µmol/liter T2 including 100,000 cpm 125I-labeled T2 for 30 min at 37 C with liver or muscle homogenate in the presence or absence (blank) of 50 µM PAPS in 0.2 ml PE buffer (33). The reactions were stopped by the addition of 0.8 ml 0.1 M HCl, and the mixtures were analyzed for sulfate formation by chromatography on Sephadex LH-20 minicolumns as previously described (33). Sulfation in reaction mixtures with PAPS was corrected for background radioactivity detected in the corresponding Sephadex LH-20 fractions of the blanks. Incubations were carried out in triplicate.

Estrogen (E2)-SULT activity was analyzed by incubation of 1 nM 3H-labeled E2 for 30 min at 37 C with liver homogenate in the absence (blank) or presence of 50 µM PAPS in 0.2 ml PE buffer with 1 mM dithiothreitol (23). The reactions were stopped by addition of 0.8 ml ice-cold water, and the mixtures were extracted with 2.5 ml dichloromethane. Sulfate formation was quantified by counting 0.5 ml of the aqueous phase. Enzymatic sulfation was adjusted for background radioactivity estimated in the blanks.

Statistical analysis

Data were analyzed using the statistical program SPSS 10.0.7 for Windows (SPSS, Chicago, IL). Logarithmic transformations were applied to normalize variables and to minimize the influence of outliers when appropriate. All analyses were done on the whole group as well as on subgroups treated or not treated with thyroid hormone. Data were analyzed using one-way ANOVA tests, with a post hoc Fisher’s least significant difference test for multiple comparisons, Mann-Whitney U tests, and linear regression analyses when appropriate. Correlation coefficients represent Spearman’s correlation coefficients. Statistical significance was assumed for P < 0.05.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Insulin therapy did not affect serum T4S levels and hepatic SULT activities

The baseline characteristics of the patients who were treated with conventional or intensive insulin therapy are shown in Table 1Go. There was no difference in age, gender, body mass index, stay on the ICU, need for thyroid hormone treatment, or iodothyronine levels between the two treatment groups. Neither T4S nor hepatic T2- and E2-SULT activities were different between the conventional and intensive insulin treatment groups.

Characteristics of the patients who were treated or not treated with thyroid hormone are shown in Table 2Go. Serum T3 and T4S but not serum T4 levels were higher in patients who were treated with thyroid hormone (7) (Table 2Go). T2- and E2-SULT activities were not different between the two treatment groups.


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  		TABLE 2. Descriptive statistics of the patients who were treated and who were not treated with thyroid hormone (TH)

 
Correlation analysis of T4S with D1 and SULT activities

Compared with the reference values in our lab (5.3–29.3 pmol/liter; mean, 17.3 pmol/liter; SD, 6.0 pmol/liter, determined in 172 healthy references) and compared with values that have been described by others (19 ± 1.2 pmol/liter, mean ± SE) (12), T4S levels were significantly elevated in the patients in this study (P < 0.0001). As described earlier, serum T4 and liver D1 activity were significantly lower than in healthy controls (7). Liver D1 activity showed a strong, negative correlation with serum T4S (R = –0.53; P < 0.001) and with the T4S/T4 ratio (R = –0.62; P < 0.001) (Fig. 1Go). T2-SULT activity was not correlated with serum T4S or the T4S/T4 ratio, nor was E2-SULT activity (Table 3Go).



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  		FIG. 1. Correlation analysis of liver D1 activity and serum T4S (A) and T4S/T4 ratio (B). Liver D1 showed a significant negative correlation with T4S (P < 0.001) and with T4S/T4 ratio (P < 0.001). No distinction was made in this figure between patients who received thyroid hormone treatment and patients who did not. R represents Spearman’s correlation coefficient.

 

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  		TABLE 3. Correlation analysis of liver D1 and T2-SULT activity and serum thyroid hormone levels

 
Similar to hepatic D1 activity (7), high E2-SULT activity was associated with low serum rT3 levels, and T2-SULT activities showed a negative trend with serum rT3 levels (Table 3Go). Hepatic D1 was positively correlated with T2-SULT activity (R = 0.29; P = 0.02) and with E2-SULT activity (R = 0.39; P = 0.003). The association of E2-SULT activity with serum rT3 was not entirely caused by the positive relation of E2-SULT and D1 activity, because a trend toward lower rT3 levels remained in a multivariate analysis (P = 0.07 for D1 and P = 0.08 for E2-SULT activity). Furthermore, T2- and E2-SULT activities were positively correlated (R = 0.65; P < 0.001).

Relation of T4S and SULT activities and cause of death

Similar to hepatic D1 activity (7), hepatic T2- and E2-SULT activities showed a significant correlation with cause of death, being lowest in the patients who had died of a cardiovascular collapse, with successive increases in the patients who had died of multiple organ failure (MOF) with sepsis or MOF with systemic inflammatory response syndrome and being highest in the patients who had died of severe brain damage (ANOVA P = 0.001 for T2-SULT and P = 0.002 for E2-SULT activity) (Fig. 2Go, A and B). Serum T4S levels did not correlate with cause of death (Fig. 2CGo).



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  		FIG. 2. Relation of hepatic T2-SULT (A) and E2-SULT activities and of serum T4S levels (C) with cause of death. Patients were divided into four different groups based on cause of death: 1, Cardiovascular collapse (n = 5); 2, MOF with sepsis (n = 21); 3, MOF with SIRS (n = 14); 4, severe brain damage (n = 4). Hepatic T2- and E2-SULT activities but not serum T4S levels showed a significant relation with cause of death (P < 0.01). P values are for trends. Data represent means ± SEM. SIRS, Systemic inflammatory response syndrome.

 
Relation of T4S and SULT activities with ICU stay and liver and kidney function

Although the number of days that a patient received intensive care before he/she died was not correlated with hepatic D1 (P = 0.45), T2-SULT (P = 0.21), and E2-SULT activities (P = 0.70), length of ICU stay was correlated with higher levels of T4S (Fig. 3Go). High plasma levels of total bilirubin on the last day were associated with low hepatic T2-SULT activity (Fig. 4AGo) and D1 activity (7) and with high levels of serum T4S (Fig. 4BGo). E2-SULT activity was not correlated with plasma bilirubin levels (P = 0.34). Plasma urea and plasma creatinine on the last day were not associated with serum T4S or hepatic SULT activities (data not shown).



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  		FIG. 3. Correlation analysis of serum T4S levels and the number of days that a patient received intensive care. The number of days was positively correlated with T4S levels (P = 0.005). No distinction was made in this figure between patients who received thyroid hormone treatment and patients who did not. R represents Spearman’s correlation coefficient.

 


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  		FIG. 4. Correlation analysis of hepatic T2-SULT activity (A) and serum T4S levels (B) with plasma total bilirubin levels on the last day. T2-SULT activity showed a significant negative correlation with bilirubin levels (P = 0.04), whereas T4S levels were positively correlated (P < 0.001). No distinction was made in this figure between patients who received thyroid hormone treatment and patients who did not. R represents Spearman’s correlation coefficient.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
No differences in serum T4S or hepatic SULT activities were found between critically ill patients who were treated with intensive or with conventional insulin therapy. In these critically ill patients, T4S levels were significantly elevated compared with healthy references. Furthermore, hepatic D1 showed a strong negative correlation with serum T4S and T4S/T4 ratio, whereas SULT activities were not correlated with these parameters. Cause of death was significantly correlated with hepatic T2- and E2-SULT activities, the latter being highest in the patients who died of severe brain damage and lowest in the patients who died of a cardiovascular collapse. A longer period of intensive care was associated with higher levels of T4S, and high levels of bilirubin were associated with low T2-SULT activities and high levels of T4S.

Insulin therapy did not affect serum T4S or hepatic SULT activities, which is in agreement with previous studies in which we found no effect of insulin therapy on serum thyroid hormone levels and tissue deiodinase activities (7, 34). It should be noted, however, that the current study involved postmortem samples. Because insulin therapy has a beneficial effect on both morbidity and mortality (27), the possibility of a selection bias (sicker patients in the studied group receiving intensive insulin therapy) cannot be excluded.

Despite low levels of serum T4, T4S levels were increased in these patients, which can be a result of an increased production and/or a decreased clearance. D1 is the enzyme responsible for the breakdown of T4S, and in previous studies it has been shown that critical illness is associated with a decreased D1 activity (1, 5, 7, 20, 34). The strong negative correlation of hepatic D1 activity with serum T4S and with the T4S/T4 ratio suggests that a decreased liver D1 activity plays an important role in the increase of T4S levels during critical illness (12). Interestingly, T4S levels were highest in patients who were treated with thyroid hormone. Treatment consisted of a combination of T4 and T3, and patients who were treated had higher levels of T3 and similar levels of T4 compared with patients who were not treated. Although T3 is known to stimulate D1 expression, D1 activities were similar between the two treatment groups, suggesting that other factors than D1 contributed to the increased T4S levels in patients treated with thyroid hormone. There might have been a greater availability of free T4 in these patients, although serum T4 levels were not significantly different from patients who were not treated with thyroid hormone. Because there was also no difference in SULT activities between the two groups, a low expression of transporters such as Na-taurocholate cotransporting polypeptide and different organic anion transporter polypeptides, which mediate the hepatic uptake of iodothyronine sulfates, may be an explanation (35, 36, 37).

T4-SULT activity in liver is low, and it is therefore not possible to measure T4-SULT activity directly in liver homogenates (24). Because the SULTs show overlapping substrate specificity, and T2 is the preferred substrate for native liver SULTs (20, 23, 24), we used T2, and not T4, as a substrate in our experiments. hSULT1E1 is the only known SULT so far catalyzing T4 sulfation, although it equally prefers T2 and rT3 over T3 and T4 (23). Because this enzyme has a much higher affinity for estrogens than for iodothyronines, we also measured hSULT1E1 using E2 as a substrate. No relation of hepatic T2- and E2-SULT activity was observed with serum T4S or with the T4S/T4 ratio. Obviously, this does not exclude a relation of in vivo T4-SULT activity and serum T4S levels.

All SULTs use PAPS as the sulfate donor (16, 17, 18). This makes sulfation expensive in terms of cellular energy, because two molecules of ATP are required to synthesize one molecule of PAPS (38, 39). In this study, SULT activities were determined in the presence of excess of exogenous cofactor. This study therefore does not provide any information about changes in the natural availability of PAPS in critical illness, when most patients have a negative energy balance, as a possible mechanism for regulation of SULT activity. Similarly, changes in the availability of SO42– during critical illness may also regulate SULT activities in these patients.

T2- and E2-SULT activities were significantly correlated with cause of death, in a pattern similar to hepatic D1 activity (7), and were not correlated with length of ICU stay. In a previous study, we assumed that liver D1 expression in patients who died acutely from severe brain damage approximates that in healthy subjects (7). This was supported by the findings that liver D1 expression of these patients was similar to D1 activity observed in normal liver obtained from patients undergoing surgical removal of hepatic tumors. In this study, T2- and E2-SULT activities were also highest in patients who died acutely of severe brain damage. T2-SULT activities were in the same order of magnitude as we observed previously in cytosol of normal liver (24), suggesting a down-regulation of T2- and E2-SULT activities during critical illness. This low expression of hepatic SULTs during critical illness may have contributed to the increased rT3 levels in these critically ill patients, because hSULT1E1 is by far the best SULT for rT3 sulfation, and sulfation of E2 is highly correlated to sulfation of rT3 in human liver (23) (Kester, M. H. A., T. J. Visser, unpublished observations). In this study, low hepatic SULT activities were associated with high serum rT3 levels, independent of liver D1 activity. Nevertheless, it might be that other factors such as severity of disease, which may affect both E2-SULT activity and serum rT3 levels in parallel, cause this effect.

A longer period of intensive care was associated with higher levels of T4S, suggesting that also the duration of disease may be important in the increase in T4S during critical illness. High levels of bilirubin were associated with a low T2-SULT and D1 activity (7) and with high T4S levels. An impaired liver function may result not only in a lower sulfation of iodothyronines but also in a decreased degradation of the sulfated iodothyronines, with the net effect being an increase in T4S levels. There was no such relation for high levels of urea and creatinine, suggesting that the relation was specific for liver and not caused by a more general organ failure.

In conclusion, serum T4S levels in critically ill patients were clearly elevated compared with normal values. This study demonstrates that the decreased activity of liver D1 during critical illness appears to play an important role in the increase in serum T4S levels, because there was a strong negative correlation of hepatic D1 activity with serum T4S and with the T4S/T4 ratio, whereas hepatic SULT activities were not correlated with these parameters.


   Acknowledgments
 
We acknowledge the medical and nursing staff of the Leuven ICU for their help in completing this study.


   Footnotes
 
This work was supported by ZonMw Grant 920-03-146 (R.P.P.) and by the Belgian Fund for Scientific Research (G.0144.00; G.3C05.95N), the Research Council of the University of Leuven (OT 99/33), and the Belgian Foundation for Research in Congenital Heart Diseases to G.V.d.B., who is also holder of an unrestricted Novo Nordisk Chair of Research on Insulin in Critical Illness.

First Published Online September 27, 2005

Abbreviations: D1, Type I deiodinase; E2, estrogen; ICU, intensive care unit; MOF, multiple organ failure; PAPS, 3'-phosphoadenosine-5'-phosphosulfate; SULT, sulfotransferase; T2, 3,3'-diiodothyronine.

Received April 20, 2005.

Accepted September 20, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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