Changes in body composition after treatment of primary hypothyroidism with levo-thyroxine

Body Composition of Patients with Primary Hypothyroidism Evaluated by Dual-Energy X-ray Absorptiometry and its Changes After Treatment with Levo-Thyroxine. Ariel Sánchez, MD, PhD;;* María Rosa Ulla, MD;^ Ricardo Capozza, PhD.º Abstract: Body composition of 30 patients with primary hypothyroidism (28 women, 2 men; age
range: 24-77 years) was studied with dual-energy X-ray absorptiometry (DXA). Nineteen patients were overweight, of which 11 were obese. Their lean body mass (LBM), fat mass (FM), and total body bone mineral content (TBBMC) were compared with the same components found in controls matched for age, sex, and body mass index (BMI). Each component also was expressed for every patient as sd (z) score above or below the mean found among normal subjects. Hypothyroid patients’ body composition did not differ from that found among euthyroid controls. Overweight patients had significantly higher LBM (P < 0.05) and FM (P < 0.01) Z- scores than lean patients. A significant positive correlation (P < 0.05) was found between BMI and FM, FM z-score, and LBM z-score, while TBBMC z-score was positively correlated with FM. TSH levels did not correlate with any of the components. Eighteen patients were studied again 2 months after reaching euthyroidism. In average, body weight decreased 2.8 kg, and LBM decreased 3.9 kg (P < 0.01). LBM significantly decreased in the trunk, abdomen, and limbs. TBBMC and FM were unchanged, although %FM rose from 45.2±9.2 to 48.9±8.6 (P < 0.02). Body composition of untreated hypothyroid patients is similar to that found among euthyroid controls. FM and LBM are significantly correlated with BMI. Correction of hypothyroidism produces a modest but significant weight loss at the expense of LBM, which decreases in both lean and obese patients, and in all anatomical regions. FM does not change significantly after treatment, but %FM increases, calling attention to the need of complementary intervention (ie, diet and exercise), especially in obese hypothyroid patients. Key words: hypothyroidism; body composition; DXA; obesity; treatment; levo-thyroxine.
(The Endocrinologist 2004; 14:321-328). *From: Centro de Endocrinología, Rosario; ^Centro Privado de Endocrinología, Osteología y Metabolismo, Córdoba; and ºCentro de Estudio del Metabolismo Fosfocálcico (CEMFOC), Universidad Nacional de Rosario, Argentina. Reprints: Ariel Sánchez, MD, PhD, Centro de Endocrinología, San Lorenzo 876, 1er. Piso, 2000 Rosario, SF, Argentin Studies of body composition in hypothyroid patients are scant and have included just a few subjects. Besides, only rarely have the changes induced by hormone replacement therapy been documented. In 1966, Kyle et al. published their observations in two hypothyroid patients whose body composition was studied by underwater weighing and calculation of body water with antipyrine or radioisotopes.1 After administration of dessicated thyroid, 120-180 mg/day, lean body mass (LBM) decreased In 1970 a review on nutrition and endocrine disorders noted that in hypothyroid patients body weight was inversely proportional to the severity of myxedema, and that it fell to subnormal leves with replacement therapy. The authors also suggested that lean mass is not diminished in hypothyroidism, and that fluid retention is always present in hypothyroid patients of all ages.2 In the same decade, using total-body neutron activating analysis, Cohn et al. were able to detect low lean mass in 3 of 5 hypothyroid patients. Body weight decreased after treatment along with total body potassium, suggesting a decrease in lean mass.3 Recently, studies using electrical impedance have documented higher fat mass in patients with acute hypothyroidism,4 and increased body fat in patients with chronic hypothyroidism than in control subjects, along with relatively unaffected LBM.5 We decided to study the body composition of hypothyroid subjects and the changes induced by treatment with oral levo-thyroxine sodium (L-T4), by means of dual-energy x-ray densitometry (DXA), which uses the four- compartment model (fat, fat-free mass, water, and mineral). It is considered to be an excellent method as a result of its precision.6,7 Besides, it offers an additional major advantage compared to the traditional approaches to the assessment of body composition because different corporal regions can be studied.6 It is an noninvasive method with negligible amount of radiation PATIENTS AND METHODS
Thirty adult patients with primary hypothyroidism (28 women and 2 men, age range: 24-77 years) were studied before the initiation of oral L-T4. The diagnosis of hypothyroidism was based on clinical symptoms and signs, elevated serum thyrotropin (TSH) levels, and reduced serum thyroxine (T4). Estimated duration of the hypothyroid state ranged from 6 to 12 months. Nineteen patients were overweight —with body mass index (BMI) >26 kg/m2— of which 11 were obese (BMI >30). The causes of hypothyroidism were autoimmune chronic thyroiditis in 21 patients, thyroid surgery for benign nodular goiter in 3, and thyroid irradiation with 131I for diffuse toxic goiter in 6; time elapsed between surgery or radioactive iodine administration and onset of hypothyroidism ranged from 5 to 9 years. Autoimmune chronic thyroiditis was diagnosed by the presence of elevated serum titers of thyroid anti-microsomal and/or anti-thyroglobulin antibodies, determined by particle agglutination. Nine of the women were postmenopausal (range: 6-25 years since menopause); none was receiving estrogen replacement therapy. Five patients were on anti- hypertensive medication (enalapril in two, nifedipine in three), which was Twelve patients were lost to follow-up. Eighteen patients were studied again after reaching clinical and biochemical euthyroidism by means of gradually increasing doses of oral L-T4. The time for achievement of euthyroidism (both clinical and biochemical, with normal serum T4 and TSH levels) was variable for each patient, and it ranged from 4 to 10 months. During that period, patients maintained their usual diet and daily activity. Serum total T4 and TSH were determined by radioimmunoassay using commercial kits, in different clinical laboratories; normal reference ranges were 4.5-12.5 µg/dL, and 0.5-5.0 µU/mL, respectively. Each patient attended the same laboratory for follow-up biochemical determinations. The mean (± standard deviation) initial values of serum T4 and TSH were, respectively, 1.8±1.0 µg/dL (range: 0.1-4.0) and 98.0±55.7 µU/mL (range: 25.0-242.0). Biochemical determinations during follow-up were done 2-3 months after the last L-T4 dosage adjustment. Final daily oral dose of L-T4 was 1.74±0.31 µg/kg. Body composition was studied with DXA using Norland XR-26 equipment (Fort Madison, WI) with software version 2.2.5. The equipment was calibrated daily using a spine phantom provided by the manufacturer; analysis of long- term precision showed a coefficient of variation (CV) of 0.43%. LBM is calculated by subtracting the TBBMC from the fat-free mass (FFM). The CV in 2 lean euthyroid postmenopausal women and 2 obese euthyroid men studied 10 times each along a short time span was 0.6% for total body mass (TM), 2.9% for LBM, 3.5% for FM, and 1.9% for TBBMC. FM was expressed in absolute (kg) as well as relative terms (as percent of TM). Each patient’s initial body composition was calculated as z-score for each compartment, as follows: (A – B)/C, where A is the subject’s amount of tissue (LBM, or FM, or TBBMC), B the mean value of that tissue mass found in a control group of normal subjects of the same sex and age, and C the standard deviation found in the same control group. Published data of body composition in 815 normal subjects (308 males and 507 females, aged 15 to 83 years), studied with the same equipment, were used for the calculations.8 The amount of body fat and other components in different anatomical areas (trunk, abdomen, and limbs) was determined in fourteen patients before and after treatment using a newer version (2.5.3) of the software. The following regions are automatically defined: head, trunk (which includes chest, abdomen, and pelvis), and limbs (arms and legs). The abdomen was an operator-defined region of interest, the upper and lower limits of which were the top of the first lumbar vertebra, and the bottom of the fourth, respectively.9 Re-analysis of the scans from the remaining four patients could not be done due to accidental damage to the diskettes where data was stored. Patients were weighed on a clinical scale immediately prior to the whole body scan. The second scan was performed in each patient 2 months following achievement of a normal serum TSH. The protocol was approved by the Bioethics Committee of one of the intervening institutions. Results were analized using the computer program Statistica (StatSoft Inc., 1995; Tulsa, OK). ANOVA was used to determine differences between groups; Student’s t test was applied for paired differences; and the association between variables was evaluated by simple correlation. P < 0.05 was considered to indicate statistical significance. Body Composition in the Hypothyroid State
Lean and overweight patient did not differ significantly in age (42.7±14.2 vs 49.7±15.9 years, respectively), initial serum T4 (1.61±0.73 vs 1.89±1.14 µg/dl) or serum TSH (114.7±71.6 vs 98.3±63.9 µU/ml). In the present series, patients with normal BMI had similar body composition that non-obese euthyroid controls (Table 1). Likewise, body composition of obese hypothyroid patients did not differ from that found in obese euthyroid controls (Table 2). As expected, LBM and FM z-scores were significantly higher in obese than in non-obese hypothyroid patients (Figure 1). Mean total bone mineral z-score did not differ significantly between lean and overweight hypothyroid patients (Figure 1). TABLE 1. Comparison of Body Composition Between Lean Hypothyroid Patients (n =
11) and Healthy Control Subjects (n = 122).
Hypothyroid
P
Patients
Subjects

TABLE 2. Comparison of Body Composition Between Obese Hypothyroid Patients (n =
19) and Obese Control Subjects (n = 33).
Hypothyroid
P
Patients
Subjects
Figure 1:

FIGURE 1. Mean z-scores for body mass index (BMI), lean body mass (LBM), fat mass
(FM) and bone mineral content (BMC) in lean (white bars) and overweight (black bars)
hypothyroid patients (*, P < 0.05; **, P < 0.01).
In the complete series of hypothyroid patients studied (n= 30), a significant positive correlation was found between BMI and FM, FM z-score, and LBM z-score (P < 0.05), whereas total bone mineral content z-score was positively correlated with FM (P < 0.05) (see Table 3 and Figure 2). Serum TSH did not correlate with any of the components of total body mass.
TABLE 3. Correlations of Measured Variables in Pooled Cases (Lean and Obese
Hypothyroid Patients).
BMI-z
LBM LBM-z
FM FM-z
TBBMC-z
BMI, body mass index; LBM, lean body mass; FM, fat mass; TBBMC, total body bone mineral
content; NS, not significant.




FIGURE 2. Correlation between lean mass z-scores and BMI in 30 untreated
hypothyroid patients. Squares represent lean subjects; circles represent overweight
and obese patients.
Changes in Body Composition After Thyroid Hormone Replacement
Serum levels of T4 and TSH were normalized after treatment (Table 4). Body weight and LBM decreased significantly (P < 0.01) after achievement of euthyroidism (Table 4; Figure 3). Mean weight decreased 2.8 kg, whereas mean lean mass decreased 3.9 kg. FM did not change significantly in absolute terms (kg), but the percentage of fat rose from 45.2±9.2 to 48.9±8.6 (P < 0.02; Table 4). There were no significant changes in TBBMC or in the ratio TABLE 4. Changes in Body Composition After Thyroid Hormone Replacement Therapy
(n = 18).
Hypothyroidism
Euthyroidism
P
LBM, lean body mass; FM, fat mass; TBBMC, total body bone mineral content; NS, not significant. FIGURE 3. Changes in body weight (full line), lean mass (dashed line) and fat mass
(dotted line) in 18 hypothyroid patients after replacement therapy with L-T4.
When the variations of each compartment were analyzed in different body areas, no significant changes in FM or bone mineral content were found in any of the regions considered (Tables 5 and 6), while lean mass decreased TABLE 5. Changes in the Fat Content (in kilograms) of the Trunk,
Abdomen, and Limbs After Treatment of Hypothyroidism (n = 14).
Hypothyroidism Euthyroidism
P

TABLE 6. Changes in Bone Mineral Content (in grams) of the Head,
Trunk, and Limbs After Treatment of Hypothyroidism (n = 14).
Hypothyroidism Euthyroidism
P

TABLE 7. Regional Changes in Lean Body Mass (in kilograms) After
Treatment of Hypothyroidism (n = 14).
Hypothyroidism
Euthyroidism
P
The decrease in lean mass induced by thyroid hormone replacement occurred in both lean and overweight patients (Figure 4).
FIGURE 4. Individual changes in LBM after replacement therapy with L-T4 in 18
hypothyroid patients (full lines represent obese patients, while dashed lines represent
patients with normal body weight).
There was a high positive correlation between gravimetric (scale) weight and total mass determined by densitometry (r = 0.98; P < 0.0001). DISCUSSION
Sixty years ago Plummer observed that only 62% of 200 hypothyroid patients defined by a low basal metabolic rate were overweight.10 Probably, most of the excess weight was edema fluid and not fat tissue.11 In Plummers’ series normalization of basal metabolic rate by thyroid extract resulted in a modest weight loss, averaging 6.5 kg. Two recent studies reached a similar conclusion: thyroid hormone replacement in hypothyroid patients produces a small initial decrease in weight, that is regained by most patients within 1-2 years.12,13 Experimentally induced hypothyroidism in rats results in significant increase in total body fat content.14 Hypothyroidism seems to induce a decrease in lipogenesis, in both the liver and white adipose tissue;11 but, on the other hand, there is a simultaneous decrease in lipolysis, apparently due to decreased sensivity to catecholamine stimulation and enhanced sensitivity of FM has been found to be higher than in controls in both the acute hypothyroid state4 and patients with long-standing hypothyroidism,5 by electrical bioimpedance. In the latter study, Seppel et al. evaluated 26 patients with untreated hypothyroidism, all with normal BMI, and compared their body composition with that found in 26 controls matched for age, sex, and height. However, patients weighed in average 10% more than controls, which probably accounts for the higher fat mass found in them.5 In our series, DXA did not detect significant differences in FM between hypothyroid patients and controls matched for age, sex, and BMI (Tables 1 and 2). Following normalization of thyroid status with oral L-T4, our patients lost a modest amount of weight, averaging 3 kg, but FM did not change significantly, either in the whole body or in the different anatomical regions (Tables 5 and 6). The proportion of fat increased from 45 to 49% (P < 0.02, Table 4). It is interesting to point out that in former hypothyroid patients receiving replacement therapy, Langdahl et al. found that FM was increased by 21% with respect to a sex- and age-matched control group; the increase was 48% in premenopausal women, and 24% in pre- and postmenopausal women taken together.15 However, in another report on thyroidectomized patients during TSH- suppressive thyroxine therapy, body composition estimated by electrical impedance was not significantly different between patients and controls.4 This discrepancy can be explained by changes in resting energy expenditure (REE) depending on the dose of L-T4 administered and the resulting degree of TSH suppression: REE can be reduced as much as 17% with serum TSH increases between 0.1 and 10 µU/mL.16 Such changes can potentially alter energy balance, body weight and body composition in the long run. The term LBM is frequently used in body composition research, but there is no consensus on how to define this component.17 It is usually assumed to consist of proteins, structural (or essential) lipids, water, glycogen, and nonosseous material; it includes the extracellular fluid, stromal vascular cells of adipose tissue, cell membranes, intracellular fluid, and all the cytoplasmic organelles within the adipocytes. Cohn et al., using neutron-activating analysis, found low lean mass in 3 of 5 hypothyroid subjects.3. Lean mass of hypothyroid patients was found to be relatively unaffected in 26 untreated patients studied by Seppel et al. using electrical bioimpedance.5 In the present series, hypothyroid patients studied by DXA did not have had significantly different LBM when compared to euthyroid controls matched for age, sex, and BMI (Tables 1 and 2). LBM z-score was positively correlated with BMI, but not with FM or FM z-score (Table 3, Figure 2). Thus, LBM seems to be variable among hypothyroid patients, and is probably dependent on the degree of obesity and the severity and duration of the hypothyroid state; however, in this series there was no correlation between lean mass and serum TSH level. There are occasional reports of increased muscle bulk by CT scanning in hypothyroid patients, that can be explained by hypertrophy of type I muscle fibers, interstitial edema, and increased glycogen content.18 Muscle pseudohypertrophy occurs in hypothyroid children and is due to accumulation of glycosaminoglycans.19 In accordance with previous reports that used different methods to assess body composition1,3 lean mass measured by DXA decreased in our patients (both lean and obese) following thyroid hormone replacement therapy (Figure 4). The decrement averaged 4 kg (Table 4, Figure 3), and it represented approximately 28% of total weight loss. Human obesity is associated with an increase in lean mass as well as in fat. Slow weight loss with a regimen not including substantial physical exercise induces a moderate loss of lean mass, which accounts for approximately 11% of the total mass lost, as assessed by DXA.20 Programs for the treatment of obesity based on exercise have been found to conserve lean tissue and favor loss of fat mass.21 Although careful evaluation of caloric intake and levels of energy expenditure was not carried out in this study, patients maintained their customary activities and usual diet during follow-up. The high percentage of LBM lost by our patients after treatment with L-T4 far exceeded that usually seen in obese patients who reduce weight; besides, lean patients also lost lean mass. Measurement of LBM by DEXA is based on the assumption of a constant hydration of lean tissue, and fluid retention may lead to its overestimation.7,22 Ultrastructural studies have demonstrated a decrease in the type I mean fiber area following treatment of hypothyroidism.18 This, along with loss of fluid and glycosaminoglycans (myxedema), is probably the anatomical basis of the observed decrease in lean mass after achievement of euthyroidism that we and others have documented. According to total bone mineral z-scores, only 3 lean and 2 obese women, and one man, had osteopenia initially; all 5 women were premenopausal. TBBMC z-scores showed positive correlation with fat mass, but not with BMI. Fat is one of the sites of aromatization of androstenedione to estrone in women;23 higher levels of estrone among women with increased fat mass could explain the association observed here between fat mass and TBBMC z-scores. In the present series, total bone mineral did not change significantly after the correction of hypothyroidism (Table 4). There are conflicting data in the literature regarding the effect of treatment with thyroid hormones on bone mass: some (but not all) studies have found a deleterious effect of TSH-suppressive therapy on BMD. A recent meta-analysis on this matter which evaluated 41 controlled cross-sectional studies, including 1250 patients, confirms this conclusion: suppressive therapy is associated with BMD decreases in the lumbar spine, the hip, and all other sites, in postmenopausal (but not in premenopausal) women. Conversely, replacement therapy is associated with bone loss (spine and hip) in premenopausal, but not in postmenopausal women.24 Since our hypothyroid patients received L-T4 starting with small doses that were carefully titrated upwards until achievement of normal serum T4 and TSH levels, it is not surprising to find conservation of total bone mineral after a relatively short period of hormone replacement. Treatment of hyperthyroid patients causes changes in FM and LBM that are specular with respect to those observed among hypothyroid patients following thyroid hormone replacement.25,26 Correction of thyrotoxicosis allows recovery of TBBMC after 1-2 years of euthyroidism.27 Although 6 patients in the present series had a past history of thyrotoxicosis, which had been corrected by therapeutic doses of radioactive iodine, they had developed hypothyroidism several years later, after a long period of normal thyroid status. In conclusion, body composition in hypothyroid patients is variable. FM and LBM are increased in obese hypothyroid patients, but not to a higher degree than among obese euthyroid controls. LBM z-score among obese hypothyroid patients is significantly higher than in lean patients, and it is significantly correlated with BMI. Finally, correction of hypothyroidism with L-T4 produces a modest but significant weight loss, at the expense of LBM, which decreases significantly in both lean and obese patients, and in all regions considered (trunk, abdomen, and limbs). TBBMC and FM are unchanged after treatment, but percent fat increases, calling attention to the need of complementary intervention such as diet and exercise, especially in obese Acknowledgements
We thank the colleagues who referred patients for this study (Drs. S. Godoy, D. Schwarzstein, R. Parma, A. Menichini, M. Grigioni), and the technicians Laura Echenique and REFERENCES
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