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DOI: 10.1530/EJE-08-0519
European Journal of Endocrinology, Vol 160, Issue 2, 207-214
Copyright © 2009 by European Society of Endocrinology
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CLINICAL STUDY

Increased reverse triiodothyronine is associated with shorter survival in independently-living elderly: the Alsanut study

E Forestier1,2, S Vinzio1,2, R Sapin2,3, J L Schlienger1,2 and B Goichot1,2

1 Service de Médecine Interne et Nutrition, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Avenue Molière, 67098 Strasbourg Cedex, France2 Faculté de Médecine,, 4 rue Kirschleger, 67085 Strasbourg Cedex, France3 Laboratoire de Biophysique, ULP/CNRS UMR 7191, Hôpital Civil, 67091 Strasbourg Cedex, France

(Correspondence should be addressed to B Goichot; Email: bernard.goichot{at}chru-strasbourg.fr)


   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 Declaration of interest
 References
 
Objective: Increased reverse tritiodothyronine (T3) used to be described as a part of euthyroid sick syndrome (ESS). It was demonstrated to be associated with increased mortality in acutely ill patients. It can also be found with low or normal T3 in non-severely ill subjects but its significance remains unclear.

Patients and design: The Alsanut study included a representative sample of 440 independently-living subjects aged 65 or over constituted between January 1988 and September 1989. Past and current medical history and nutritional data were collected at inclusion. Baseline thyroid hormone (TSH, FT4, FT3 and rT3) serum levels were measured. Life status was determined on 1 December 2005.

Results: Of the 374 elderly subjects included in the final analysis, 52 had abnormal TSH (43 with hyperthyroidism, nine with hypothyroidism) and 80.7% had died by 1 December 2005. There was no statistical difference in survival between subjects according to thyroid function (P=0.54). Of the 322 elderly subjects with normal TSH, mortality rate was 81.1%. ESS was found in 3.4%, whereas 8.1% of the participants displayed elevated rT3 with normal FT3. Time to death was strongly related to rT3 (P<0.0001) and FT3 (P<0.0001) in a univariate analysis. After adjusting for other confounding variables, rT3 was the only thyroid hormone associated with shorter survival (P=0.014).

Conclusions: RT3 was the only thyroid hormone associated with shorter survival in a representative population of independently-living elderly. In these subjects, isolated elevated rT3 might be an equivalent of ESS, reflecting declining health.


   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 Declaration of interest
 References
 
Acute and severe chronic non-thyroidal illnesses are frequently associated with non-specific disturbances of thyroid function tests called ‘euthyroid sick syndrome’ (ESS) (1, 2). This syndrome is characterized by a constant decrease in tri-iodothyronine T3 and free T3 (FT3) serum concentrations. It can be associated with more variable disturbances of the other thyroid parameters, such as an increase in reverse T3 (rT3), a decrease in T4 and free T4 (FT4), and even a decrease in TSH concentrations in the most severe forms (3, 4).

Substantial data suggest that there are probably several kinds of ESS, depending on the type of associated diseases, severity or acute, or chronic form. In acute ESS, it was shown that the decrease in T3 and the increase in rT3 are related to mortality (5, 6, 7, 8, 9, 10). In non-acutely ill elderly, T3 and rT3 are often decreased and increased respectively, but many questions remain as to whether these disturbances are due solely to aging or to poor health status (11, 12).

Alsanut was an epidemiological study conducted in the late 1980's that aimed at determining the prevalence of thyroid dysfunction and ESS in 440 independently-living elderly (13). It individualized a group of subjects who displayed elevated rT3 with FT3 and TSH within normal ranges. They were characterized by lower energy intake, older age, and lower cholesterol level. Sixteen years later, the mortality data were collected in this population to explore the relationship between baseline clinical and biological characteristics and survival, with a focus on rT3.


   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 Declaration of interest
 References
 
Subjects

The representative sample of independently-living subjects aged 65 or over in Bas-Rhin (northeastern France) who were included in the Alsanut study was constituted as previously published (13). Briefly, subjects were randomized based on electoral lists with stratification on age, gender, and settlement (rural versus urban). Deceased persons and those refusing to participate in the study or give a blood sample were replaced by a subject with the same characteristics taken from an additional list. Inclusion in the study was spread over a period of 20 months from January 1988 to September 1989.

A total of 440 subjects accepted to participate in the study. They were subsequently interviewed by an investigator and completed a questionnaire on their medical history (diabetes, cardiac failure, hypertension, cerebrovascular disease, ongoing neoplastic disease), current treatment, smoking status, and mean energy and nutrients intake on a 3-day food record. Body mass index was calculated for each person.

No subject was undergoing corticosteroid therapy. Seven subjects taking amiodarone were excluded from the final analysis, as well as 13 others who were on synthetic thyroid hormones or antithyroid drugs.

Biological data

For each subject a blood sample was taken in the morning at inclusion. TSH, thyroid hormones (free T4 (FT4), free T3 (FT3), and reverse T3 (rT3)), total and high density lipoprotein (HDL) cholesterol, and prealbumin serum concentration were measured. TSH and thyroid hormones were assayed using radioimmunological commercial kits (Behringwerke AG, Marburg, Germany for TSH; Amerlex MAB, Kodak diagnostic, UK for FT4; Amerlex M, Kodak diagnostic, UK for FT3; and Biodata, Montecelio, Italy for rT3). Normal ranges that had been determined on subjects from various European centres were provided by the manufacturer. They were 0.4–4.5 mU/l for TSH; 13.2–28.8 nmol/l for FT4; 3.3–8.22 nmol/l for FT3; and 0.14–0.53 nmol/l for rT3. Total cholesterol and HDL cholesterol were assayed using the caloric enzymatic method (CHOP-PAP) on a Hitachi 737 analyser. Normal ranges were 1.25–1.85 g/l (males) and 1.35–2.10 g/l (females) for total cholesterol, more than 0.40 g/l (males) and more than 0.50 g/l (females) for HDL cholesterol, and 220–350 mg/l (males), and 200–300 mg/l (females) for prealbumin.

Technical problems concerning biological data led to the exclusion of 18 subjects.

Mortality data

The registry offices of the towns where the subjects were born were consulted to determine if the subjects were living or had died after 1 December 2005. This information was not available for 28 subjects leading to their exclusion from the final analysis. Dates of death were collected but cause of death could not be assessed in this way.

Statistical analysis

Unless otherwise stated results are expressed as mean±S.D. Because of its markedly skewed distribution, TSH was natural-log transformed before analysis. The Pearson's product-moment correlation coefficient was used to evaluate the association among continuous variables. The study population was further divided into three tertiles based on serum rT3 levels. The intergroup comparisons were determined by ANOVA test. Cumulative survival was analyzed using the Kaplan–Meier method, with every continuous variable divided into tertiles. Multivariate survival analyses were performed with a Cox model. They were adjusted first for age and sex, and other major confounding factors (total and high-density lipoprotein cholesterol levels, prealbumin level, systolic and diastolic blood pressure, body mass index, smoking status, pre-existing disease such as diabetes mellitus, ischemic heart disease, cardiac failure, cerebrovascular disease, and cancer) based on literature data or univariate survival analysis (P<0.05) were subsequently added to the multivariate models. The relative strength and interdependence of these relationships were investigated by an automatic backward stepwise selection. Hazard ratios (HRs) with a 95% confidence interval were used to estimate the relative risk of death. HRs are expressed by a 1-unit increase in the parameter at baseline. Receiver operator characteristic (ROC) curve analyse were carried out for different parameters (age, total cholesterol, HDL cholesterol, prealbumin, TSH, and thyroid hormones) using occurrence of death versus non-occurrence as the outcome measure. All tests were two-sided, and P<0.05 was considered statistically significant. Data were analyzed using SPSS 15.0 (SPSS Inc., Chicago, IL, USA).


   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 Declaration of interest
 References
 
Thyroid status and its relationship with mortality

Of the 374 persons included in the study, 322 had normal TSH levels between 0.4 and 4.5 mU/l. Forty three subjects had TSH levels below 0.4 mU/l (between 0 and 0.39 mU/l) with normal FT4 in 34 subjects corresponding to subclinical hyperthyroidism. TSH was above 4.5 mU/l in nine subjects (between 5.5 and 45 mU/l), with normal FT4 in three of them reaching the criteria for subclinical hypothyroidism. The characteristics of the three groups, defined according to TSH levels, did not differ significantly (data not shown).

On this whole sample, survival was not associated with FT4 (r=0.007; P=0.89) and TSH (r=–0.043; P=0.4) levels. Conversely, a significant correlation existed with rT3 (r=–0.288; P<0.001) and FT3 levels (r=0.200; P<0.001). Kaplan–Meier analysis did not show any significant difference in survival between the three groups defined by TSH levels (P=0.54) or by FT4 levels (P=0.80), unlike FT3 (P<0.001) and rT3 (P<0.001; data not shown).

Characteristics of euthyroid subjects according to rT3 and FT3 levels

Three hundred and twenty-two subjects with normal TSH level were included in the following analysis, 168 males and 154 females with a mean age of 76.3±7.4 years. Their characteristics are summarized in Table 1. Briefly, 33 (10.2%) subjects suffered from diabetes and 115 (35.7%) from hypertension. A history of stroke, cardiac failure, or ischemic heart disease was noted in 21 (6.5%), 33 (10.2%), and 44 (13.7%) people respectively. Fifteen (4.7%) persons had been treated for neoplastic disease, 113 (35.1%) subjects were active or former smokers.


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  		Table 1 Characteristics of subjects by reverse triiodothyronine (T3) and free T3 level.

 
Mean TSH and FT4 at inclusion were 1.29±0.68 mUI/l and 20.24±3.69 nmol/l respectively. Two hundred and eighty-eight subjects (89.4%) had normal FT3 and rT3 levels. Eleven (3.4%) participants had low FT3 (between 1.85 and 3.23 nmol/l) corresponding to the definition of ESS, with normal rT3 levels in seven, and rT3 above the normal range (between 0.68 and 1.50 nmol/l) in four. Twenty-six subjects (8.1%) had elevated rT3 (between 0.54 and 1.50 nmol/l) with normal FT3. The remaining biological data are reported in Table 1.

On 1 December 2005, 261 (81.1%) subjects had died and 61 (18.9%) were alive. Median survival was 2755±352 days (~ 7.5±1.0 years). It was significantly shorter for participants with isolated elevated rT3 or low FT3 compared with those with normal hormone levels (P=0.001). Eighteen (5.6%) died within 1 year of the inception, 24 (7.4%) between 1 and 2 years, 29 (9%) between 2 and 3 years, 25 (7.8%) between 3 and 4 years, and 226 (70.2%) after 4 years or later.

Subject characteristics by rT3 tertile

The population was divided into three tertiles based on rT3 serum concentrations: the lowest tertile, less than 0.31 nmol/l (n=104); the middle tertile, 0.31 to 0.41 nmol/l (n=109); and the highest tertile, more than 0.41 nmol/l (n=109).

The characteristics of these three groups are shown in Table 2. Increasing age and FT4 concentrations were noted throughout the rT3 tertiles, whereas an inverse relationship between energy intake, cholesterol concentrations, prealbuminemia, and rT3 serum levels was found. Ischemic heart disease was more frequently reported by subjects with the highest rT3 levels.


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  		Table 2 Characteristics of subjects divided into three tertiles according to reverse triiodothyronine (T3) level.

 
Relation between baseline parameters and survival

In a Kaplan–Meier analysis, shorter survival was significantly related to increased rT3 (P<0.0001; Fig. 1, part A) and decreased FT3 (P<0.0001; Fig. 1, part B), whereas there was no relation with TSH and FT4 (P=0.328 and 0.169 respectively). Other variables significantly associated with early death in univariate analysis were advanced age (P<0.0001), male gender (P=0.047), history of ischemic heart disease (P=0.01), heart failure (P=0.001), and stroke (P<0.0001), low total (P<0.0001) and HDL cholesterol levels (P=0.02), and low prealbuminemia (P<0.0001).


Figure 1
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  		Figure 1 Cumulative survival by tertile of baseline reverse T3 (RT3) (part A) and free (FT3) (part B) serum concentrations (Kaplan–Meier analysis). RT3 lowest tertile correspond to serum concentrations lower than 0.31 nmol/l, middle tertile to concentrations between 0.31 and 0.41 nmol/l, and the highest tertile concentrations greater than 0.41 nmol/l. FT3 lowest tertile correspond to serum concentrations lower than 3.16 nmol/l, middle tertile to concentrations between 3.16 and 4.10 nmol/l, and the highest tertile to concentrations greater than 4.10 nmol/l.

 
In multivariate analysis (adjusted for age and gender), increased rT3 (P<0.001) and low FT3 (P<0.001) remained associated with shorter survival. This association disappeared for FT3 (P=0.34) after adjustment for other variables associated with early death in a univariate analysis, whereas it remained unchanged for rT3 (P=0.001; Table 3, model A). In a full model including rT3 (P=0.014), early death was also significantly related to low caloric intake (P=0.016), low prealbuminemia (P=0.002), decreased total (P=0.005) and HDL cholesterol (P=0.035), and history of ischemic heart disease (P=0.054), stroke (P=0.037), and diabetes (P=0.019; Table 3, model B). It is noteworthy that the association between rT3 and survival was stronger after exclusion of participants with low FT3 serum levels (P<0.0001).


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  		Table 3 Factors associated with all-causes mortality (Cox regression).

 
To test if the association between rT3 and survival was due to increased short term mortality, subjects who died within 1, 2, and 3 years of inception were subsequently excluded from analysis. The results did not change when subjects who died within 1 or 2 years of inception were excluded (P=0.003 and 0.001 respectively in multivariate analysis). Conversely, they were significantly modified after the exclusion of the 71 subjects who died within 3 years of inception since association between survival and baseline rT3 in the remaining subjects completely disappeared in multivariate analysis (P=0.199).

Predictive value of rT3 for mortality

A ROC curve was created to evaluate the predictive value of rT3 and other variables significantly associated with shorter survival in multivariate analysis (Fig. 2). The area under the curve was the highest for rT3. With the restrictive upper normal value of 0.53 nmol/l used in our study, its specificity was 98.4%, whereas sensitivity was only 11.5%. The value of 0.38 nmol/l, corresponding to the mean of rT3 in the population gave a specificity of 85.2% and a sensitivity of ~51%.


Figure 2
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  		Figure 2 Receiver operating characteristic curves of the biological markers significantly associated with shorter survival in a multivariate analysis. The area under the curve is 0.34 (95% confidence interval [CI], 0.27–0.40) for total cholesterol, 0.40 (95% CI, 0.32–0.49) for high density lipoprotein (HDL) cholesterol, 0.37 (95% CI, 0.29–0.44) for prealbumin, 0.38 (95% CI, 0.31–0.45) for free T3 (FT3) and 0.75 (95% CI, 0.69–0.81) for reverse T3 (RT3).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
Declaration of interest
 References
 
In a population of independently-living elderly euthyroid subjects, the Alsanut study demonstrated a significant relationship between rT3 and shorter survival while taking into consideration other critical factors such as age, gender, medical history, nutritional parameters, and energy intake. Conversely, FT3, FT4, and TSH were not associated with survival in these subjects after adjustment for confounding variables.

Apart from the most severe clinical pictures of hypo- and hyperthyroidism, conflicting data exist on whether or not thyroid dysfunction is associated with increased all-causes mortality (14, 15, 16, 17). Major methodological differences (populations'age; length in years of follow-up; co-morbidities considered in the statistical analysis; etc.,) could explain these contradictory results. Similarly, recent meta-analysis did not allow formal conclusion of this possible association (18, 19). In our study, their was no significant difference in survival between subjects according to thyroid function. However, the relatively small size of our sample prevents us from adding any reliable proof to this debate.

Conversely, our results concerning the association between survival and rT3 in euthyroid subjects certainly deserve much more attention. RT3 is an isomere of T3 with no demonstrated biological activity. It results from the transformation of T4 through inner ring deiodination by types 1 and 3 deiodinases in peripheral tissue. By contrast outer ring deiodination by types 1 and 2 deiodinases leads to activation of T4 into T3 (20, 21). Clinical studies illustrated that rT3 serum concentrations increase with age (1, 12, 13), the presence of multiple diseases (12), and may be influenced by energy intake (despite conflicting results) (13, 22). However, whether these variations should be taken into account is still unknown.

Increased rT3 is usually considered as a part of ESS. This entity is characterized by a constant decrease in T3 serum concentrations, and variable abnormalities of other thyroid hormone levels (4). It is secondary to severe acute (e.g., septic shock, myocardial infarction) (8, 9) or chronic (e.g., cancer, advanced acquired immunodeficiency syndrome) (23, 24, 25) diseases and it has been demonstrated to be a predictor of increased mortality (6, 18). As expected in our population of independently-living non-severely ill people, ESS was rare, occurring in only 3.4%. The one-step method used for FT3 measurement in our study has been criticized because it tends to underestimate FT3 concentrations in ESS, compared with the reference method that is equilibrium dialysis (26). Consequently, the number of participants with ESS might be even lower in our study, and we can be sure that subjects with normal FT3 serum levels did not have ESS.

Despite normal FT3, 26 participants had increased rT3 levels (>0.53 nmol/l, the upper normal range used in our study), accounting for 8.1% of the assessable subjects. At baseline, they had older age, lower energy intake, and lower cholesterol levels compared with other participants (13). Similarly, Van den Beld identified more than 25% of healthy independently-living elderly men with a similar hormone profile in a study with a less restrictive upper normal range (12). He showed that these people with isolated increased rT3 had lower physical performance. Thus, in addition to classically defined ESS, elevated rT3 appears far from rare in non-severely ill subjects and seems to be associated with a poor global health status.

In acutely ill patients, rT3 was described as an independent parameter predictive of mortality, as after acute myocardial infarction or in patients hospitalized in intensive care (8, 9). In independently-living subjects, mortality data are weak. Only Van den Beld evaluated this parameter in his study and did not find an association between increased rT3 and shorter survival (12). However, he showed an association between low FT4 and 4 year survival. Conversely in our study, rT3 was the only thyroid hormone associated with survival in non-severely ill elderly. With the restrictive upper normal range of 0.53 nmol/l used in our study, rT3 has a specificity as high as 98.5% in predicting early death, whereas its sensitivity is quite low at 11.4%.

Our results appear reliable given the quality of the initial selection of subjects, which was carefully done by stratification and randomization in an epidemiological view, giving a perfectly representative sample of the elderly Alsatian population. Additionally, the long follow-up makes it possible to interpret these results over the long term. No definite explanation can be advanced to differentiate our results and Van den Beld's. The main difference between the two populations resides in the fact that he included only men, whereas ours was composed of both genders. Van den Beld's subjects were also probably in better health since none of them were treated for systemic, infectious, inflammatory, or malignant disorders at the time of investigation contrary to ours (13). Otherwise, the mean age of the participants is similar, the size of the two samples is comparable, and the results are based on a single hormone measurement at inclusion in both studies.

Finally, although we suggested previously that rT3 could be a reliable hormonal parameter to appreciate nutritional status (13), we can now propose that elevated rT3 may reflect more than simply the nutritional status but rather a poor overall health status given the relationship between survival and rT3. This is supported by the relation between rT3 and survival resulting from increased short-term mortality, since it disappears after exclusion of the subjects who died within 3 years of inception. We can support Van den Beld's hypothesis that isolated elevated rT3 may be a catabolic state preceding ESS (12). We could also hypothesize that this condition might not be a pre-stage but rather an equivalent of ESS in the independently-living elderly. Unfortunately, the design of our study does not formally answer this question. A prospective evaluation of subjects with the highest rT3 levels would certainly help to verify whether they develop true ESS throughout standardized biological follow-up and whether death occurs earlier compared with control subjects.

The mechanisms that could explain isolated elevated rT3 remain to be identified. One can hypothesize that they may be at least partly similar to those involved in ESS. These mechanisms remain unclear (reduced activity of type 1 deiodinase (1, 9, 21), clearance of T3 and rT3 by the liver (12), tissular transport of thyroid hormones, nuclear, and post-transcriptional phenomena (4, 27)...). Several are in fact probably involved, depending on the underlying disease, and prove that ESS is a heterogenous condition. To explain isolated elevated rT3, it could be hypothesized, for example, that the reduced hepatic clearance of rT3 would appear before, or would be predominant, at this stage on the reduced activity of type 1 deiodinase, which also leads to decreased FT3. Other mechanisms than those leading to non-thyroidal illness are thought to be involved. As previously mentioned, they may be related to age and energy intake which impact on rT3 concentrations. However, according to our results, others are also probably independent of the aging process or nutritional parameters.

Apart from rT3, most other variables associated with survival in our study were previously reported. Nevertheless, the link with nutritional data must be emphasized. Low energy intake, prealbuminemia, and both HDL and total cholesterol were strong predictors of early death in a multivariate analysis including adjustment for BMI. Several authors have published conflicting results on total cholesterol in free-living elderly. Most studies pointed out hypocholesterolemia as an independent predictor of mortality (28, 29), whereas others did not (30). Some investigations also underlined the close link between usual nutritional markers such as prealbumin or albumin, cholesterolemia, and health status (31, 32, 33). Our study provides additional arguments to these observations. Nevertheless, it should be noted that according to the ROC curve created with our results, rT3 was the best parameter to predict shorter survival among those tested.

In conclusion, our study demonstrates a strong association between rT3 and survival in a population of independently-living elderly subjects regardless of other confounding factors. This ‘high rT3 syndrome’ might precede an overt ‘low T3 syndrome’ or might be an equivalent of it in the non-severely ill elderly. Thus, rT3 could deserve to be assessed in elderly subjects with normal TSH. Additional studies are nevertheless necessary to confirm these results and explore the pathophysiological pathways that could lead to elevated rT3.


   Declaration of interest
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Declaration of interest
References
 
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.


   Funding
 
This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.


   Acknowledgements
 
We thank Linda Northrup for his help in the preparation of the manuscript.


   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Declaration of interest
 References
 

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Received 15 October 2008
Accepted 9 November 2008




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