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Original Studies |
Departments of Radiology (L.L.), Endocrinology (K.S., E.N.), and Medicine (L.S., A.-K.L.) and the Wallenberg Laboratory (M.O.), Sahlgrenska University Hospital, University of Goteborg, S-413 45 Goteborg, Sweden
Address all correspondence and requests for reprints to: Dr. Lars Lönn, Department of Radiology, Sahlgrenska University Hospital, S-413 45 Goteborg, Sweden. E-mail: lars.lonn{at}medfak.gu.se
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Abstract |
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Introduction |
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Thyroid hormones have fundamental effects on thermogenesis and body weight, but few and contradictory studies have examined changes in body composition after treatment of hyper- or hypothyroid subjects. In hypothyroid subjects, body water has been reported to be reduced when measured with bioelectrical impedance (6), but increased when measured with isotope dilution techniques (7). Treatment of hypothyroid patients have resulted in decreased (8) or increased (6) fat-free mass (FFM) when measured with densitometry (8) and bioelectrical impedance (6), respectively. Body fat (BF) was reduced during treatment, as measured with both techniques (6, 8).
Hyperthyroid patients have been reported to have normal extracellular but reduced intracellular water (7). During short term experimental hyperthyroidism, FFM is reduced when estimated from skinfolds (9) and body densitometry (8). During treatment of hyperthyroid patients, FFM, bone mineral mass, and muscle mass increase, as judged from 40K and 49Ca measurements (10, 11).
The reports in the literature on the effects of thyroid hormones on body composition seem to be more unequivocal with respect to hyper- than hypothyroidism. However, the effects of increased and decreased levels of thyroid hormones on subcompartments of AT and FFM are still largely unknown.
The aim of the present study was to examine dual energy x-ray absorptiometry (DXA)- and CT-determined changes in body composition of hyperthyroid patients before and after 3 and 12 months of euthyroid conditions.
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Experimental Subjects |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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). The diagnosis of hyperthyroidism was
based on clinical assessment, biochemical findings (free
T4, total T3, and TSH), radioiodine uptake
measurement, technetium scintigraphy, and measurement of basal
metabolic rate (BMR). TSH was below and free T4
as well as total T3 were above the reference
ranges in all patients (Table 1). Four patients were smokers (no. 1, 4,
5, and 6). No patient had cardiac complications or was taking
medication likely to influence fluid or electrolyte balance.
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). One patient (no. 5, Table 1), who was being treated for depression,
had her last examination postponed until 24 months after established
euthyroidism. Eight patients had diffuse and one patient (no. 2, Table 1) toxic nodular goiter. The three patients selected for surgery
received pretreatment with methimazole for at least 2 months. Two of
these patients (no. 4 and 9, Table 1) were operated upon before and 1
patient (no. 6, Table 1) was operated upon after the 3 month
examination. One patient was treated with methimazole (15 mg, twice)
only, and five patients were given radioiodine (Table 1). Four patients
(no. 3, 5, 6, and 7, Table 1) were given propranolol immediately after
the baseline examination. The ß-blocking treatment was discontinued
when euthyroidism was established.
The patients were followed every second to fourth week during the first
year, and supplementation with levothyroxine was immediately started as
soon as TSH approached or passed the upper normal reference value.
Except for patient 5 (Table 1), all subjects received levothyroxine
substitution. Based on all available TSH concentrations, a maximum TSH
value during the entire observation period was defined for each
subject.
Informed consent was obtained from all patients. The study was approved by the ethics and radiation committees at the Medical Faculty, University of Goteborg (Goteborg, Sweden).
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Materials and Methods |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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Serum free T4 was determined with ligand
analog RIA (Amerlex-M free T4, Amersham
International, Aylesbury, UK), total T3 was
determined with a polyethylene glycol-assisted double antibody RIA
(T3 RIA double antibody, Diagnostic Products Corp., Los Angeles, CA), and TSH was determined with an
immunoradiometric assay (Behring Werke, Marburg, Germany). Reference
values are given in Table 1. The within-assay coefficients of variation
were 2.6%, 2.4%, and 8.0%, respectively.
Body weight and height
At baseline and 3 and 12 months after established clinical euthyroidism body weight was measured in the morning to the nearest 0.1 kg using a calibrated electronic precision platform scale (F 300S, Sartorius, Goettingen, Germany). Height was measured with the patient barefoot to the nearest 0.01 m using a wall-mounted stadiometer. Body mass index (BMI) was calculated as body weight (kilograms) over height (meters)2. At the time of diagnosis, the patients were asked to estimate their body weight 1 yr earlier; this is the self-reported premorbid body weight.
DXA
DXA was performed using a Lunar DPX-L scanner (Lunar Corp., Madison, WI). The system has an x-ray source and a K-edge filter to achieve a congruent beam of stable dual energy radiation. The total body examination was performed in the fast mode, i.e. the scan speed suggested by the system software for each subject. BF, lean tissue mass (LTM), total bone mineral content (BMC), and bone mineral density (BMD) were analyzed using software version 1.31. FFMDXA was calculated as LTMDXA + BMCDXA. For validation purposes, DXA-estimated body weight, calculated as LTMDXA + BMCDXA + BFDXA, was compared with measured body weight. It should be noted that the DXA algorithms make no use of body weight when determining BF, LTM, or BMC.
The precision error of the scanner used (system 7156), as determined from double examinations in 10 healthy subjects (age, 42 ± 9 yr; BMI, 73.8 ± 3.0 kg/m2) who were repositioned between each examination, was 1.7% for BF, 0.7% for LTM, 1.9% for total body BMC, and 1.5% for total body BMD.
CT
Tissue areas were determined with the subject in a recumbent position with a Philips Tomoscan 350 (Philips, Eindhoven, The Netherlands) using the following settings: 120 kV, 302 mA, and slice thickness of 12 mm. Scan 1 was taken in the midthigh region half-way between the knee joint and the iliac crest, scans 2 and 3 were taken in the L3–L4 and L4–L5 discs, respectively, and scan 4 was taken at the midliver level. From scan 1 the sum of the tissue areas of both legs is reported. The average tissue areas from scans 2, 3, and 4 are referred to as trunk areas. The effective dose equivalent per examination was 0.4–0.8 mSv. The images from the CT scanner were transferred to a separate analyzing unit (Philips SAVS). Tissue areas were determined as previously described (12) with the following precision errors calculated from double determinations: sc AT (0.5%), ip AT (4.6%), retroperitoneal AT (12.1%), the sum of ip and retroperitoneal AT (1.2%), muscle plus skin (0.3%), visceral organs (0.7%), and dense skeleton (3.4%).
Calorimetric methods
BMR was determined by indirect calorimetry in a metabolic chamber as previously described (13). BMR was registered in the fasting state after 1 night in the chamber and after morning voiding. The registration occurred in the recumbent position over 40 min without allowing the patient to fall asleep. Reference values for BMR, considering sex, age, height, and weight, were predicted from the equations suggested by Schofield (14). Food intake was reported, and energy intake was calculated at diagnosis and at the end of the study using a previously validated dietary questionnaire (15).
Statistical methods
Statistical calculations were carried out on a Vax 4100 computer (Digital Equipment, Maynard, MA) using the Minitab statistical program, version 9 (16). Comparisons were performed by two-tailed paired t test or Wilcoxon nonparametric test. Descriptive statistics were given as the mean ± SD for all variables except TSH, for which median and range were used. P values have been corrected for multiple comparisons according to the method of Bonferroni (17), i.e. the crude P value obtained from the test was multiplied by the number of comparisons performed. Resulting P values greater than 1.0 were set at 1.0. P < 0.05 was regarded as significant.
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Results |
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At diagnosis, body weight (mean ± SD) was
67.6 ± 14.0 kg (Table 1), which was 7.4 ± 5.0 kg below the
self-reported premorbid body weight (75.0 ± 14.8 kg;
P = 0.0022). TSH was below (median, 0.004; range,
0.000–0.020 mU/L) and free T4 (79.5 ± 38.0
pmol/L) as well as total T3 (6.1 ± 2.3
nmol/L) were above the reference ranges in all patients, demonstrating
the hyperthyroid state (Table 1).
Changes in body weight, thyroid hormones, energy expenditure, and energy intake after treatment
Body weight had increased 2.7 ± 3.1 kg after 3 months
(P = 0.06) and 8.7 ± 1.8 kg after 1 yr
(P < 0.001) to 76.3 ± 13.4 kg. The self-reported
premorbid body weight was thus restored after 1 yr of clinical
euthyroidism (Table 2). During treatment
there were no clinical signs of edema.
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In a separate analysis, the maximum TSH level during the entire observation period for each subject was ascertained. The maximum TSH value ranged from 1.3–17.3 mU/L, with five subjects having values above the upper reference level (4.0 mU/L). In six of the nine cases, the maximum TSH value was observed before the 3 month examination. Patients with TSH levels close to or above the upper reference level were given T4 within 0–2 weeks after the observed TSH elevation.
BMR was significantly higher than predicted at baseline (2087
vs. 1522 Cal/24 h; P < 0.01; Table 2). At 3
and 12 months, BMR was close to the predicted value, and in none of the
individual subjects did BMR indicate a hypothyroid status. Energy
intake, calculated from the reported food intake, was reduced
(P < 0.01) at 12 months (Table 2).
DXA measurements
At baseline, BF was 18.0 ± 6.9 kg and FFM was 48.8 ±
12.5 kg (Table 2). After 3 months of clinical euthyroidism there was a
marked increase in FFM by 2.7 ± 1.6 kg (P <
0.003), whereas BF was not changed (0.4 ± 1.8 kg;
P = NS; Table 2). After 12 months, FFM had increased
3.5 ± 1.2 kg (P < 0.0001), and BF had increased
5.3 ± 2.0 kg (P < 0.0001; Table 2). The observed
increases in BMC and BMD did not reach significance (P
= 0.082 for BMC). For the women (n = 5), the P value
was 0.056 for the 12 month change in BMC. The average increase in BMC
in the entire group over 12 months was only 0.16 ± 0.19 kg
(P = NS) and thus of little importance for the change
in DXA-determined FFM.
There was a close agreement between DXA-estimated body weight and actually measured body weight at baseline (66.8 ± 14.0 vs. 67.6 ± 14.0 kg) and after 3 (69.9 ± 12.6 vs. 70.3 ± 12.2 kg) and 12 months (75.6 ± 13.0 vs. 76.3 ± 13.4 kg) of clinical euthyroidism. On all three occasions, the correlation between DXA estimated body weight and measured body weight was 0.999 or more (not shown in tables).
Tissue area measurements with CT
At baseline, the following CT-determined cross-sectional areas (square centimeters) were observed in the trunk: sc AT, 138 ± 89; total visceral AT, 59 ± 30; ip AT, 40 ± 19; retroperitoneal AT, 19 ± 12; muscle plus skin, 139 ± 44; and visceral organs, 138 ± 26. In the thigh, the baseline areas were (square centimeters): sc AT, 198 ± 87; muscle plus skin, 230 ± 85; and femur bone tissue, 14 ± 2.2 (not shown in tables).
The relative changes in tissue areas, as determined with CT, are shown
in Fig. 1. After 3 months the major part
of the skeletal muscle increase had occurred. Thus, muscles of trunk
and thigh had increased by 11% (P = 0.002) and 18%
(P = 0.006), respectively, whereas the corresponding
increases after 12 months were 17% (P = 0.006)) and
25% (P = 0.002).
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The cross-sectional areas of visceral organs were 138 ± 26, 139 ± 18, and 140 ± 20 cm2 (P = NS) at 0, 3, and 12 months, respectively. Corresponding figures for the cross-sectional bone area of femur were 14.0 ± 2.2, 14.1 ± 2.3, and 14.2 ± 2.4 cm2 (P = NS), respectively (not shown in tables).
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Discussion |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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The reported energy intake as well as the BMR were increased at baseline. During treatment, both energy intake and energy expenditure were normalized. Evidently the decrease in energy expenditure was large enough to permit anabolism despite decreased energy intake.
The increased energy expenditure observed in this and other studies of hyperthyroidism (18, 19, 20) causes loss of weight (21, 22). The components of this weight loss have not been extensively examined with established body composition techniques. More than 70 yr ago, decreased muscle strength was documented in thyrotoxic patients (23), and by means of clinical inspection muscular atrophy has been considered typical for hyperthyroidism (24). Bayley et al. (11) evaluated body composition with 40K and 49Ca and examined hyperthyroid patients before and after 50 months of efficient treatment. A selective loss in BMC and muscle mass was suggested to be typical for hyperthyroidism (11). During recovery these abnormalities were reversed (11). As judged from skinfold technique, short term (14 days) experimental hyperthyroidism in man causes a decrease in FFM without a simultaneous reduction of total body fat (9). During recovery from Graves’ disease, most of the total body potassium is replenished during the first 10 weeks after initiation of treatment, and during this early phase the increase in body potassium per kg increase in body weight is more pronounced than later on (10). These circumstances indicate that FFM is more sensitive to early changes in thyroid hormones than BF, but in neither of these reports (9, 10) were the different subcompartments of FFM and BF studied. However, in one CT-based study, increased thigh muscle area after treatment of hyperthyroidism was demonstrated (25).
With DXA, body composition is determined at the molecular level (26) according to a three-compartment model: body weight = BF + BMC + LTM. LTM consists of proteins, structural lipids, water, glycogen, nonosseous minerals, and a small residual. LTM + BMC is equal to FFM in traditional two-compartment models. With the CT technique, body composition is examined at the tissue and organ levels (26). From tissue areas and distances between scans, tissue volumes can be calculated (12). Models at the tissue and organ levels could be expressed as body volume = lean body volume + AT volume. The lean body volume can be further organized in several tissues and organs, and each component can be converted into mass by taking the corresponding tissue density into account (12).
FFM includes not only the extracellular fluid and stromal vascular cells of adipose tissue but also cell membranes, intracellular fluid, and all cytoplasmic organelles of the adipocytes themselves. Therefore, it is formally not possible to mix information from DXA and CT examinations. In the current study a simplified CT procedure was used in which tissue areas, rather than volumes, were determined. Despite these limitations, the findings obtained with these two measuring techniques were in agreement with each other. The DXA technique showed that BF was not increased after 3 months, but was increased after 12 months. With its higher resolution, the CT technique detected an increase in ip AT, but not in sc AT, at 3 months, whereas at 12 months, sc AT had also increased. Similarly, the DXA technique detected an early and large increase in FFM. With CT, this increase was shown to be due to an increase in muscle, but not in bone tissue or visceral organs.
It should be stressed that the increase we observed in lean tissues and muscle during treatment is most likely due to both protein and water restitution. Neither CT nor DXA can separate these two constituents of lean tissues.
From other studies it is known that BMC is reduced in hyperthyroidism and recovers during treatment of hyperthyroidism (27). In the current study the BMC recovery only reached borderline significance in the total study group (P = 0.082) and in the women (P = 0.056), whereas the increase in BMC in males was not significant. Most likely the lack of significance is due to the small number of patients studied.
The increased thermogenesis in hyperthyroidism was demonstrated 100 yr ago (18) and has been confirmed repeatedly (19). The increased energy expenditure may partly be related to an elevated protein turnover. However, protein degradation predominates causing negative nitrogen balance and atrophy of skeletal muscles (20) as well as decreased muscle efficiency (25). Decreased muscle mass and decreased efficiency may be unrelated phenomena, as ß-adrenergic blockade is capable of improving muscle strength before changes in thyroid status (28).
In contrast to the situation in the rat (29), human AT lipoprotein lipase activity does not increase during recovery from hyperthyroidism (30). Instead, the lipid accumulation during recovery seems to be related to decreased lipolysis (31). The mechanism behind the early preferential recovery of visceral AT compared to sc AT after treatment of the thyrotoxic state can only be speculated upon. Previous studies have demonstrated a higher lipid turnover in visceral AT than in other fat depots, probably due to an increased innervation and blood flow as well as a higher density of glucocorticoid receptors (32). Whether thyroid hormones are directly involved in regional differences in lipid metabolism remains to be elucidated.
In conclusion, this study described previously unknown details with respect to changes in body composition during recovery from the hyperthyroid state. Skeletal muscles and visceral AT showed an early increase, whereas sc AT was not recovering during the first 3 months of euthyroidism. Visceral organs and BMC did not change significantly during the 12 months of euthyroid conditions.
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Acknowledgments |
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Footnotes |
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Received January 7, 1998.
Revised April 14, 1998.
Accepted August 17, 1998.
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