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Clinical Studies |
Division of Endocrinology (H.A-A., J.E.S.), Department of Medicine, Jewish General Hospital, McGill University, Montreal, H3T 1E2; McGill Nutrition and Food Science Centre (L.J.H.), Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada H3A 1A1
Address all correspondence and requests for reprints to: J. Enrique Silva, M.D., Jewish General Hospital, Endocrinology, Room 104, 3755 Cote-Ste-Catherine Road, Montreal, Quebec, Canada H3T 1E2. E-mail: mdsi{at}musica.mcgill.ca
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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Thyroid hormone affects energy balance by several mechanisms (see Refs. 6–8 for recent reviews). This hormone stimulates the rate of metabolism by accelerating a myriad of metabolic synthetic and catabolic pathways, which in turn increase the demands for other energy-requiring processes, e.g. transport of metabolites or ions across membranes. Thyroid hormone is also necessary for facultative thermogenesis, as it amplifies the effect of the sympathetic nervous system on thermogenic targets such as brown adipose tissue. Thyroid hormone also increases food intake. In experimental animals or patients with overt thyrotoxicosis, increased food intake is insufficient to satisfy the increased demands and there is loss of body fat and protein, in spite of the stimulatory effect of thyroid hormone on protein synthesis and lipogenesis (see Ref. 9 and references therein). Even though thyroid hormone and catecholamines interact coordinately to maintain thermic homeostasis, this interaction is disrupted in conditions where the thyroid gland functions at an abnormally high or low level. The acute response to cold may be reduced in experimental thyrotoxicosis (10), and there is evidence that the sympathetic tone is increased in hypothyroidism, whereas the opposite may occur in thyrotoxicosis (reviewed in Refs. 11, 12). While the net effect of the interplay of these factors on energy balance may be clear in extreme cases of thyroid dysfunction, this is not the case in milder forms of thyroid dysfunction, or in patients in chronic treatment with thyroid hormone, in whom the adjustment of the dose is based on serum TSH, which may or may not be a reflection of thyroid hormone action in tissues and organs relevant to energy balance.
To gain insight into this area of thyroid hormone physiology, we have examined the effect of slightly varying the dose of thyroxine on resting energy expenditure (REE) and the thermic effect of food in a group of nonselected patients in chronic treatment with this hormone. Results indicate that minor variations in the thyroid state are associated with significant changes in REE and possibly changes in the opposite direction in the thermic effect of food. The induced changes in REE correlated negatively to serum TSH levels, indicating that minor deviations of TSH from normal reflect significant physiological changes, which have the potential to become clinically relevant.
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Materials and Methods |
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Nine subjects from the outpatient clinic of Sir Mortimer B.
Davis Jewish General Hospital in Montreal, Quebec consented to
participate in the study. They were randomly incorporated in the study
as long as they were on chronic treatment with thyroxine and did not
fulfill any of the exclusion criteria [any disease that could affect
energy expenditure or the ability to be tested (e.g. heart
or respiratory disease, liver insufficiency, major psychiatric
disorders); concomitant endocrine disease; drugs that affect energy
expenditure such sympathomimetic or antiadrenergic drugs; other
hormones; heavy smoking or significant caffeine intake (i.e.
more than two cups a day of coffee or tea)]. They were all females
with ages ranging between 25–72 yr. Six were postmenopausal, but none
was taking estrogens at the time of the study; in the premenopausal
women, testing was done in the week following the end of menses. Their
body mass indices, percent body fat, and initial thyroid related blood
tests are all shown in Table 1
. They were instructed to
maintain their life styles including diet and physical activity during
the length of the study. They had been on T4 for at least 3
yr, took no other medications, and were free of any other acute or
chronic ailment.
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). The purpose of the study was explained to the subjects,
verbally and in writing, following which they consented to have their
T4 dose modified and agreed to the ensuing testing. The
T4 doses and the sequence in which these were given are
displayed in Table 1. Based on the initial free T4 and TSH
levels, the daily dose of thyroxine was randomly increased or decreased
between 25 and 50 µg, equivalent to 15–66% above or below the
previous dosage, with the intention of moving TSH slightly under or
over the normal range (see Table 2).
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Subjects were examined and subjected to the investigations described below while on their usual dose of T4 (on which they had been for at least 4 months) and between 6 and 8 weeks after the dose had been changed. (This 2-week interval allowed flexibility to schedule the test sessions). The examiner carrying out the investigative work up was blinded to the subjects’ diagnoses and doses of thyroxine. During each visit, at the end of each dose period, patients were evaluated for symptoms and signs of thyroid dysfunction using a standard protocol (13) slightly modified. Subjects were instructed to fast after the evening meal the night before the visit.
a) Blood testing
Blood testing included total and free T4, total serum T3, TSH, T3 resin uptake, antithyroid antibodies, routine blood chemistry (SMA-12), total-, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol, triglycerides, angiotensin converting enzyme (ACE), and sex hormone binding globulin (SHBG). Specimens were obtained 24 h after the previous dose of T4. Free T4 two step assay, T3 radioimmunoassay and TSH immunoradiometric assay were from Clinical Assays, INCSTAR Corp., Stillwater, MN. ACE was from Sigma Diagnostics, St. Louis, MO. SHBG was measured with an immunoradiometric assay from Diagnostic Products Corporation (DPC), Los Angeles, CA. Inter- and intra-assay coefficients of variation (CV) in the range of values found in the study subjects were as follows (all in %): free T4: 6.4, 6.5; T3: 6.3, 7.0; TSH: 6.3, 3.7; ACE: 3–5; 1–2; SHBG: 3.1–6.9, 2.8–3.6. All tests were performed in the Clinical Chemistry laboratory of the Jewish General Hospital. All samples were assayed together for Free T4, TSH, ACE, or SHBG to avoid inter-assay variation. Lipids were analyzed in the fresh, unfrozen sample. Free T4 and TSH were also measured in this sample to obtain a preliminary result known only to the investigator in charge of changing the thyroxine doses (J.E.S.). The rest of the samples were stored in aliquots, frozen at -20 C for the definitive assays.
b) Metabolic investigations
Fat-free mass (FFM) was measured by bioelectrical impedance analysis (BIA) before each metabolic study, using the BIA-101 Analyzer (RJL Systems, Inc., Detroit, MI) and the equations derived by Kushner et al. (14). Energy expenditure was measured using the Deltatrac ventilated hood indirect calorimeter (Summit Technologies, Oakville, Ontario), calibrated and manipulated as described elsewhere (15). Subjects reported after a normal sleep and in the fasting condition to a special study room in the Nutrition Laboratory of the Royal Victoria Hospital, between 0700 and 0900 h (16). Only the subject and the tester (usually H.A.) were present in this pleasant, semi-darkened, well-ventilated, and thermoregulated (22–24 C) room. Before the first metabolic measurement, all subjects underwent a training session to familiarize them with the measurement experience. After the subject had rested quietly for 30 min, a clear plastic hood was placed over her head and shoulders and ventilated with room air at 38 L/min. At an appropriate signal from the subject, oxygen and carbon dioxide sampling was begun. Data from the first 5 min of these measurements were discarded. CO2 and O2 volumes (VCO2; VO2) for each of the subsequent 15 min were averaged and converted to kilocalories (Kcal) using the Weir equation (17) and expressed on a per day basis. After the training session, either immediately or a few days later, REE was measured as in the training session. Average REE measured during the training session did not differ from the first formal measurement (1308 ± 225 vs. 1308 ± 222 (SD) kcal/day; P > 0.5 by paired t test). The absolute variation from the training to the formal session was 1.83 ± 0.8% (SEM). Immediately after the REE measurement was finished, subjects sat up and, over 20 min, consumed 75 g of orange-flavored hydrated glucose (Glucodex, Rougier, Inc., Chambly, Quebec) previously equilibrated at room temperature. They then reclined again under the hood and measurements were resumed for 180 min, allowing 10 min interruptions after 55 and 120 min to break the monotony or to void, if desired. The thermic effect of glucose (TEG) was calculated as an excess of energy expenditure over the REE: the data during the 180 min following the test meal were integrated, and the average REE obtained immediately before was subtracted from it. The resulting excess Kcal was expressed as percent of the energy in the test meal (300 Kcal). Over 85% of the thermic responses occurred during this time, particularly with a relatively low calorie test meal of 300 Kcal (18, 19).
Statistical analysis
Numerical data including resting energy expenditure (REE),
thermic effect of glucose (TEG), and blood test results were submitted
to various statistical analyses and transformations using Minitab
statistical software, student’s edition, release 8, Minitab Inc. and
GraphPad Prism 2.0, Sorrento Valley, San Diego, CA. Statistical
analyses included one way analysis of variance (ANOVA), homogeneity of
variance (Bartlett’s test), Student’s t test, Neuman-Keuls
test, and linear and nonlinear correlations. For correlations between
TSH and REE, serum TSH concentrations were log transformed and both
variables tested for linear correlations. All correlations satisfied
the test for linearity after transformation. TSH has been used here as
a sensitive indicator of thyroid hormone tissue availability. Log
transformation of TSH is justified owing to the nonlinear response with
the thyroid status in the range studied. Significance was established
at a P value of less than 0.05. Data derived from the
questionnaire of symptoms and signs were analyzed using Fisher’s Exact
Test after dividing the patients according to their serum TSH
concentrations in low (<0.45 mU/L), normal (0.45–4.5 mU/L), and high
(
4.5 mU/L).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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shows the age, diagnoses, body mass index (BMI), percent
body fat, initial serum levels of free T4, total
T3, TSH, and initial and subsequent doses of T4
of all patients. Purposely, the initial dose of T4 was
randomly increased or decreased. Body mass index (BMI, weight/height
squared, Kg/m2) ranged from 21.2–39.5 and body fat from
24–46.4% of body weight. Initial free T4 was within
normal limits in all patients and so was TSH in all but two patients
(nos. 1 and 5). Table 2 shows the effect of the dose on free
T4, T3, and TSH. Changes in the thyroxine dose
induced significant variations in TSH levels in all patients, with a
16-fold ±5, excursion between the lowest and the highest dose. TSH
values ranged from 0.05–18 mU/L, with nine values below and six values
above the normal range. Induced changes in serum free T4
and T3 were smaller and for the most part the
concentrations of these hormones remained within the normal range. Both
free T4 and TSH correlated significantly with the dose, but
this was not the case with serum T3. The correlations are
better seen in Fig. 1. In every patient, except no. 5,
free T4 increased with the dose. This correlation was
maintained even when the data of all patients were pooled r =
0.69; P < 0.001), indicating that the dose accounted
for nearly 50% of the variation in free T4 levels. In each
individual, TSH decreased as the dose of T4 increased (Fig. 1, lower panel). Serum T3 did not correlate with
either the changes in the dose of T4 or with the induced
variations in serum TSH, although when a paired test was done for the
serum T3 there was a significant difference of 0.277
± 0.086 nmol/L (P < 0.025) between the lowest and the
highest dose of thyroxine. In spite of the narrow range of changes
induced by the manipulation of the T4 dose on free
T4, serum TSH levels were significantly and negatively
related to free T4 concentrations (Fig. 2).
This is not a linear correlation, but it can be linearized by
log-transforming TSH and using 1/T4 (20). The regression
line and the corresponding error have been plotted in Fig. 2. The
r2 value for this correlation was 0.37 (r = 0.61;
P < 0.001), indicating that serum free T4
can explain 37% of the variance of TSH.
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, the values of REE and TEG are shown as a function of
TSH, which has been arranged in increasing order for each patient.
Since the main determinant of REE is fat-free mass (FFM) (21, 22), REE
and TEG were normalized by FFM and the results expressed per kg of FFM
in subsequent analyses. The inspection of this Table shows that FFM was
not affected by the manipulations of the T4 dose. In every
patient, REE decreased as serum TSH levels increased (Fig. 3, upper panel). Moreover, when the data from
all patients were pooled, there was a significant negative, linear
correlation between log TSH and REE/FFM r = -0.80,
P < 0.0001). Note that the regression line is
REE/FFM = 27.4–2.53 x log TSH, thus, the reduction of REE when
TSH moved from 0.1 and 10 mU/L TSH was approximately 17%. This range
includes the normal range and what is usually considered the
subclinical hyper- and hypothyroid range. Importantly, a similar
relationship was also obtained between initial serum TSH and the first
REE measurement (Fig. 4, upper panel). Also,
the changes in REE were proportional to the excursion in serum TSH
concentration induced by the transition from the highest to the lowest
T4 dose (Fig. 4, lower panel).
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), whereas in 3 (dashed lines in same figure), the
value moved erratically with the induced changes in TSH. Such a trend
was also observed when the TEG was plotted against TSH data grouped in
low, normal, or high as shown in Fig. 5. The analysis
showed normal distribution for TEG in the three TSH ranks. ANOVA
indicated that differences between means did not reach statistical
significance (F = 2.852; P = 0.077), but the
linear trend between the means and column rank had a P value
of 0.039.
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. In accord with high values of BMI and percent body
fat (Table 1), several patients had slightly elevated LDL cholesterol
and triglycerides and reduced HDL cholesterol. On the other hand, it is
evident that there is more variability of all these indices among
patients than within a patient in relation to her TSH levels (Fig. 6).
Regarding symptoms and signs, when these were analyzed by the Fisher’s
exact test, only a few were associated with the thyroid status as
reflected by TSH level. These included drier hair, lid puffiness, and
reduced attention span, which were associated with the highest TSH
values. There was no association between TSH level and appetite, energy
level, temperature sensitivity, memory, or sleep pattern.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It should be noted that patients were not selected, and they were quite heterogeneous regarding age, ovarian function, BMI, FFM, and nature and time of onset of the thyroid diseases motivating the treatment with T4. Thus, it is even more remarkable that potentially confounding variables did not mask the correlations between REE and the thyroid status as reflected by TSH. This plus the internal consistency of the relations between REE and initial or induced TSH level, and between the induced excursion of TSH and that of REE together indicate that REE is very sensitive in an individual to changes in the availability of thyroid hormone. In judging the sensitivity of REE to thyroid hormone, it should be recognized that only 20–25% of resting energy expenditure is thyroid hormone dependent in humans, as this is the maximal reduction seen in individuals with profound hypothyroidism (23). The sensitivity of REE to thyroid hormone is comparable indeed that of TSH secretion.
These results are also important from the standpoint of energy balance
and weight control of patients depending on exogenous T4. A
change of 5–10% in REE, as seen in our subjects when TSH moved around
the normal range (Figs. 3 and 4), is physiologically relevant. Because
about 9 Kcal excess can generate 1 gram of stored fat, a decrease in
REE of 75–150 Kcal per day, with unchanged food intake, could result
in a cumulative weight gain of several kilos in the lapse of 5–10 yr.
Thus, from a point of view of energy balance, a small deviation in TSH
in patients on exogenous T4 has the potential to be
associated with significant changes in weight and adiposity, potential
that could be realized if other physiological compensations do not
function properly or if, in the absence of these mechanisms, no
modifications are made by the patient in calorie intake or physical
activity.
Responses of REE to such small variations in the thyroid status obtained with T4 have not, to the best of our knowledge, been reported before. In a study performed in normal subjects given T3 (24), basal metabolic rate increased significantly following a short treatment with relatively small doses of this hormone, which nonetheless doubled serum T3 levels, a much greater change than the one induced in our patients serum T3. Probably more similar to our results is the observation made in infants with "subclinical hypothyroidism" (elevated TSH but within-normal-range serum T4 and T3) (25). In that report, infants with TSH greater than 7 mU/L had reduced basal metabolic rate, which improved upon treatment with T4, whereas those with TSH less than 7 mU/L were not different from controls. Notably, the differences in serum free T4 or T3 concentrations between the two groups were not statistically significant.
It is interesting also that the changes in REE did not correlate with induced variations in serum T3 or free T4, although these latter two increased significantly between the lowest and the highest dose given to each patient and free T4 correlated significantly with the dose of T4 and with TSH. These results further support the idea that the sensitivity of the tissues to thyroid hormone with regard to metabolic rate is very high. They may also suggest, as has been demonstrated in rodents, that the control of energy expenditure may depend on local mechanisms regulating the availability of T3 in target cells. In rats, brown adipose tissue thermogenesis depends largely on locally generated T3 by Type II 5' deiodinase of this tissue activated by the sympathetic nervous system (26, 27). The correlation of REE with TSH and the comparable sensitivity of both to the supply of T4 suggest that the mechanisms of regulation of REE by thyroid hormone may be similar to those involved in TSH regulation.
The thermic effect of food is another factor in energy balance. Two observations, possibly interconnected, were made in the present studies. One was the trend of TEG to correlate positively with serum TSH, and the other was that the values we obtained were low compared with those obtained in euthyroid subjects using the same or similar experimental approaches (16, 18, 28). The lack of better correlation between TSH and the thyroid status as reflected by serum TSH may derive from the comparatively large error inherent to the determination of thermic effect of food in humans (19, 28). This trend could possibly be confirmed with a larger sample. The rather low values of TEG we obtained cannot be readily attributed to our methodological approach as we followed previously established protocols and took the prescribed precautions (16, 18, 19, 28). Although possibly related to the moderate obesity of the patients (29), TEG did not correlate inversely with BMI or adiposity. Thus, we cannot exclude the possibility that the rather low figures are related to the administration of thyroid hormone, which is consistent with the trend of the TEG values to be inversely related to the magnitude of the T4 dose, as reflected in serum TSH levels. Although it may be counterintuitive that more thyroid hormone is associated with a reduction in TEG, studies in experimental animals indicate that this is possible. It has been demonstrated that sympathetic stimulation of several tissues is increased in hypothyroidism and reduced in hyperthyroidism, both in experimental animals (30, 31, 32, 33) and humans (34, 35). On the other hand, facultative thermogenesis, which is mediated by the same pathways and mechanisms as diet-induced thermogenesis, is blunted in rats made thyrotoxic with T4 (7, 10, 36). It is therefore possible that exogenous T4, particularly if given in doses high enough to reduce TSH, may decrease TEG.
In summary, we have demonstrated that small changes in T4 dose in patients chronically treated with this hormone can significantly affect REE. These changes are negatively correlated with serum TSH levels, and they occur without the dose moving serum free T4 or T3 out of the normal range and in the absence of detectable effects on other commonly used thyroid hormone action indexes or on symptoms and signs. REE demonstrated a sensitivity comparable to that of TSH as an indicator of thyroid hormone action in target tissues, with reductions in REE of as much as 17%, with serum TSH increases between 0.1 and 10 mU/L. This can not be emphasized enough, as serum TSH concentrations in this range are frequently considered clinically insignificant, and such changes in REE have the potential to affect energy balance and body weight in the long run. This potential may be realized if such reductions in REE are not offset by concomitant changes in other factors of the energy balance equation, such as reductions in food intake and increases in sympathetic tone and the thermic effect of food.
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Acknowledgments |
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Footnotes |
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Received September 6, 1996.
Revised November 5, 1996.
Revised December 30, 1996.
Accepted January 10, 1997.
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REE/FFM = 3.88+log
