REVIEW  CURRENT  OPINION      Thyroid hormone and obesity                               Elizabeth N. Pearce               ...
Thyroid hormone and obesity Pearce                                                                    (on average 1.8 kg),...
Thyroid hormone were a consequence, rather than a                 gastric bypass surgery. At baseline, TSH receptor cause,...
Thyroid hormone and obesity Pearceaddition to the effects of leptin, it has also been                 study, 24 obese and ...
Thyroid                                                                                        8. Polotsky HN, Brokhin M, ...
Thyroid hormone and obesity Pearce31. Vella KR, Ramadoss P, Lam FS, et al. NPY and MC4R signaling regulate                ...
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Hormona tiroidea y obesidad

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Hormona tiroidea y obesidad

  1. 1. REVIEW CURRENT OPINION Thyroid hormone and obesity Elizabeth N. Pearce Purpose of review To review several of the most recent and most important clinical studies regarding the effects of thyroid treatments on weight change, associations between thyroid status and weight, and the effects of obesity and weight change on thyroid function. Recent findings Weight decreases following treatment for hypothyroidism. However, following levothyroxine treatment for overt hypothyroidism, weight loss appears to be modest and mediated primarily by loss of water weight rather than fat. There is conflicting evidence about the effects of thyroidectomy on weight. In large population studies, even among euthyroid individuals, serum thyroid-stimulating hormone is typically positively associated with body weight and BMI. Both serum thyroid-stimulating hormone and T3 are typically increased in obese compared with lean individuals, an effect likely mediated, at least in part, by leptin. Finally, there is no consistent evidence that thyroid hormone treatment induces weight loss in obese euthyroid individuals, but thyroid hormone analogues may eventually be useful for weight loss. Summary The interrelationships between body weight and thyroid status are complex. Keywords body weight, obesity, thyroid INTRODUCTION modest weight loss following initiation of levothyr- Both thyroid dysfunction and obesity are highly oxine (L-T4) therapy, but all had returned to their prevalent in the general population. National data weights before treatment by 12–24 months. Eighty- suggest that hypothyroidism is present in 4.6% of seven hyperthyroid patients had lost a mean of 16% the US population, and hyperthyroidism in 1.3% of their body weights before hyperthyroidism at the [1]. Obesity rates have climbed in the USA and time of presentation; 2 years following initiation of worldwide over the last several decades; more than treatment, they had regained and slightly exceeded 30% of the US population is now classified as obese their baseline weight. A recent study of weight [2]. This review focuses on recent clinical studies change following treatment of thyroid dysfunction regarding the effects of thyroid treatments on in 57 hyperthyroid and 29 hypothyroid children weight change, associations between thyroid status similarly found that weight loss was minimal and body weight, and the effects of obesity and following treatment for hypothyroidism (mean weight change on thyroid function. 0.3 kg by the first follow-up visit) [5]. However, there was an average 7.1 kg gain in weight by the second follow-up visit following initiation of treatment WEIGHT CHANGE AFTER TREATMENT FOR for hyperthyroidism. THYROID DYSFUNCTION Weight change was followed for 1 year in Thyroid hormone increases the basal metabolic 12 overtly hypothyroid individuals [mean baseline rate [3]. Patients with overt hypothyroidism often present with a history of weight gain, and those with Boston University School of Medicine, Boston, Massachusetts, USA hyperthyroidism frequently present with weight Correspondence to Elizabeth N. Pearce, MD, MSc, Boston University loss. However, the degree of weight change with School of Medicine, Section of Endocrinology, Diabetes, and Nutrition, thyroid dysfunction, and the effects of treatment 88 East Newton Street, Evans 201, Boston, MA 02118, USA. Tel: +1 on body weight are surprisingly poorly understood. 617 414 1348; fax: +1 617 638 7221; e-mail: elizabeth.pearce@bmc. A 1984 study described weight change following org initiation of treatment for thyroid dysfunction [4]. Curr Opin Endocrinol Diabetes Obes 2012, 19:408–413 Nine of 18 hypothyroid patients experienced a DOI:10.1097/MED.0b013e328355cd6c www.co-endocrinology.com Volume 19 Number 5 October 2012Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  2. 2. Thyroid hormone and obesity Pearce (on average 1.8 kg), whereas L-T4 treatment was not KEY POINTS associated with significant weight change. On the Body weight increases following hyperthyroidism basis of DEXA scans, there was a nearly significant treatment and modestly decreases following decrease in fat mass of 5.3% (P ¼ 0.052) with hypothyroidism treatment. L-T3 treatment. In population studies, serum TSH (within the normal range) is positively associated with baseline BMI and OBESITY AND THYROID SURGERY with weight change over time. A large multicenter retrospective study of 18 825 Serum TSH and free triiodothyronone (FT3) are both patients who underwent total thyroidectomy increased in obese individuals; levels normalize with recently demonstrated that the duration of surgery weight loss. is longer in obese and overweight patients than in There is no clear effect of thyroid hormone treatment on lean patients, and surgical complications are more weight loss in obese euthyroid individuals, however, frequent [10]. However, the authors concluded that there may be a future role for thyroid hormone these differences did not seem to impact on duration analogues as an obesity treatment. of hospital stay, and therefore might not be clin- ically meaningful. A retrospective study compared weight change in 102 thyroid cancer patients fol-thyroid-stimulating hormone (TSH) 102 mIU/L] fol- lowing thyroidectomy with weight change in euthy-lowing initiation of L-T4 treatment, and compared roid patients with benign nodules or goiter whose with 10 euthyroid controls [6 ]. At 1 year (mean thyroids were not resected [11 ]. There was no differ-serum TSH 2.2 mIU/L), mean weight had decreased ence in weight or BMI change between the twosignificantly, from 83.7 to 79.4 kg (P ¼ 0.002). Dual groups at a median 5.9 years of follow-up. In anotherenergy X-ray absorptiometry (DEXA) scans demon- retrospective study, 120 patients with achievementstrated that the weight loss following initiation of of euthyroidism on thyroid hormone therapy 1 yearL-T4 was due to decreases in lean mass, with no following total thyroidectomy were compared withsignificant changes in either bone mass or fat mass; age, gender, height, menopausal status, and baselinethe authors concluded that weight loss after L-T4 weight-matched treated hypothyroid individualstreatment for hypothyroidism is mediated primarily who did not undergo thyroidectomy [12 ]. In con-by loss of excess body water. trast to the previous study, at 1 year, the thyroidec- Among hypothyroid patients, the degree of TSH tomized patients had experienced significantlysuppression achieved by L-T4 therapy does not more weight gain (3.1 vs. 2.2 kg, P ¼ 0.004) thanappear to strongly influence body weight. In a pro- the matched controls.spective study examining the effects of treatinghypothyroid patients to a TSH goal of 0.4–2 mIU/Lcompared with 2–4 mIU/L, the patients treated to ASSOCIATIONS BETWEEN THYROIDthe lower TSH target had higher resting energy STATUS AND WEIGHT AND WEIGHTexpenditure, but there was no difference in lean CHANGEor fat body mass or percentage body fat between the Recent population studies have examined the groups at 1 year [7 ]. Polotsky et al. [8 ] retrospec- effects of thyroid status on weight and on weighttively examined changes in body weight among change over time. In a cross-sectional study of 778153 athyreotic thyroid cancer survivors treated euthyroid (serum TSH 0.4–5 mIU/L) Spanish adults,with TSH-suppressive L-T4 doses (median serum serum TSH, and BMI were positively correlated, andTSH 0.05 mIU/L) for up to 5 years. There was a individuals with serum TSH levels in the highestmedian 3.2% weight gain at 3–5 years of follow- tertile had the highest BMI values [13]. However,up, despite ongoing iatrogenic hyperthyroidism, when this cohort was restricted to a subgroup of 375similar to or higher than previously published individuals without detectable serum thyroperoxi-euthyroid population values. dase antibodies, these relationships were no longer A blinded cross-over study examined the effects observed. Another Spanish study examined longi-of liothyronine (L-T3) compared to L-T4 treatment tudinal weight change in relation to baseline TSHin 14 adults with primary hypothyroidism who were levels in 784 euthyroid adults followed for 6 years already on L-T4 therapy [9 ]. Patients were treated [14]. At baseline, TSH, FT3, and free thyroxine (FT4)with L-T3 or L-T4 taken three times daily, in order to levels did not differ in obese and nonobese individ-achieve a serum TSH 0.5–1.5 mIU/L at three con- uals. Increases in FT3 were positively correlated withsecutive biweekly visits. The L-T3 treatment (for a increases in weight over the follow-up period,mean of 19 weeks) resulted in significant weight loss and the authors suggested that increases in thyroid1752-296X ß 2012 Wolters Kluwer Health | Lippincott Williams Wilkins www.co-endocrinology.com 409Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  3. 3. Thyroid hormone were a consequence, rather than a gastric bypass surgery. At baseline, TSH receptor cause, of interval weight gain. In the Norwegian and thyroid hormone receptora1 expression were Nord-Trøndelag health cohort study, associations decreased in both visceral and subcutaneous fat between baseline thyroid status, weight, and BMI deposits in obese individuals, and did not differ were investigated in 15 020 euthyroid (serum TSH by glucose tolerance. Following a 33% decrease in 0.5–3.5 mIU/L) individuals over a mean follow-up BMI at 1 year after bariatric surgery, the subcu- of 10.5 years [15 ]. In women, for every 1 mIU/L taneous fat expression of TSH receptor increased increase in baseline serum TSH, there was a 0.9 kg by 150% and the expression of thyroid hormone increase in weight and a 0.3 kg/m2 increase in BMI receptora1 increased by 70%. over the follow-up period, whereas in men, for each 1 mIU/L TSH increment, weight increased by 0.8 kg and BMI by 0.2 kg/m2. EFFECTS OF OBESITY ON THYROID STATUS The relationship between thyroid status and obesity EFFECTS OF THYROID STATUS ON FAT is likely to be bidirectional, with hypothyroidism DISTRIBUTION affecting weight and BMI, but obesity also influenc- Limited data suggest that thyroid status may influ- ing thyroid function. Thyroid function abnormal- ence adipose tissue distribution as well as the overall ities are highly prevalent in obese individuals: amount of adipose tissue present. Both thyroid hor- among 783 consecutive obese patients seen for bari- mone and visceral fat (as quantified by abdominal atric surgery evaluation, 18.1% had elevated serum ultrasound) were measured in 174 euthyroid prepu- TSH [21]. In 1976, Bray et al. [22] demonstrated a bertal children [16]. In cross-sectional analyses positive correlation between T3, but not T4, and adjusted for age, BMI, and total body fat, FT4 body weight. This observation has since been con- was independently and inversely associated firmed in multiple studies [23,24 ]. Most recently, in with visceral fat stores. In a cross-sectional study a cross-sectional analysis of data from the National of euthyroid adults with known vascular disease, Health and Nutrition Examination Survey 2007– higher serum TSH was associated with increased 2008, among 3114 euthyroid adults without a visceral fat thickness, although only among indi- history of thyroid disease, BMI and waist circum- viduals aged 67–80 years. Serum TSH was not ference were positively associated with serum TSH associated with either weight or BMI. A previous and FT3, but not FT4 [25 ]. These relationships are study in 303 healthy volunteers had demonstrated present in children as well as in adults. A recent that the amount of subcutaneous fat and the review describes four studies in which childhood subcutaneous-to-visceral fat ratio were inversely obesity was associated with moderate serum TSH correlated with free T4 levels and that TSH elevations [26 ]. In two of those studies, weight loss was positively correlated with subcutaneous fat led to normalization of serum TSH. Another recent thickness [17]. review concluded that 7–23% of obese children The effects of thyroid status on fat distribution exhibit serum TSH elevations with normal or may be explained by differential TSH receptor and/ slightly elevated FT3 levels [24 ]. In obese patients or thyroid hormone receptor expression in different with mild TSH elevations, it may be difficult to fat depots, and receptor expression seems to differ in distinguish between true subclinical hypothyroid- obese compared with lean individuals. TSH receptor ism and physiologic alterations in thyroid function; expression was recently measured in subcutaneous however, individuals with undetectable thyroid fat samples from 120 euthyroid patients [18]. Sub- antibodies and high-normal serum T3 levels are cutaneous fat TSH receptor expression was found to unlikely to have true underlying thyroid failure be increased in individuals with higher BMI. A [27,28 ]. previous study had demonstrated that thyroid hor- The reason for elevations in both TSH and T3 in mone receptora and thyroid hormone receptora1 obese individuals is not entirely clear. However, it is expression is increased in subcutaneous compared likely that leptin plays a role in regulating this with visceral fat deposits in obese, but not normal- process. Leptin, secreted by adipose cells, serves as weight patients [19]. Finally, Nannipieri et al. [20] a signal to the central nervous system regarding measured TSH receptor and thyroid hormone recep- energy balance and the presence of energy stores. tora1 expression in subcutaneous and visceral fat in Leptin promotes thyrotropin releasing hormone obese and lean patients, and then prospectively gene expression directly in the paraventricular measured TSH receptor and thyroid hormone recep- nucleus, ultimately stimulating TSH release [29– tora1 expression in subcutaneous fat samples from a 31]. Leptin may also increase T4 to T3 conversion subset of 27 obese patients before and 1 year after by deiodinases in a tissue-specific fashion [32,33]. In 410 www.co-endocrinology.com Volume 19 Number 5 October 2012Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  4. 4. Thyroid hormone and obesity Pearceaddition to the effects of leptin, it has also been study, 24 obese and overweight adults werepostulated that thyroid function abnormalities treated with hypocaloric diets and randomized toin obesity may be related to peripheral thyroid receive recombinant leptin therapy vs. placebo for hormone resistance, altered TSH bioactivity, or 6 months [42 ]. Leptin treatment was not associatedmay constitute an adaptive process designed to with differences in thyroid function as comparedincrease resting energy expenditure [34,35]. with the placebo-treated controls, suggesting that leptin alone may not mediate changes in thyroid function in response to weight loss inducedTHYROID FUNCTION CHANGES AFTER by dieting.WEIGHT CHANGEIn 1979, Danforth et al. [36] demonstrated thatshort-term and long-term overnutrition in human THYROID HORMONE AND THYROIDvolunteers resulted in increased T3, but not T4, HORMONE ANALOGUES FOR WEIGHTproduction, and that serum T3 decreased with LOSS IN EUTHYROID INDIVIDUALScaloric restriction. More recent observational stud- A systematic review by Kaptein et al. [43] identifiedies have demonstrated alterations in thyroid func- 14 studies describing the effects of T3 or T3/T4tion following weight loss in obese individuals, treatment on weight loss in euthyroid individualsregardless of the way in which weight loss is during caloric deprivation. Sample sizes were small,achieved. In a study comparing adolescent girls ranging from only five to 12 in treated groups.with normal weight, obesity, or anorexia nervosa, Thyroid hormone treatment reduced serum TSHTSH and FT3 were significantly lower in the ano- and T4 concentrations, resulting in subclinicalrexic girls and significantly higher in the obese hyperthyroidism, and there was no consistent effectgirls than the normal-weight girls [37]. Following on weight loss across studies.weight gain of more than 5%, TSH and FT3 Despite the lack of clear efficacy of thyroidincreased in the anorexic girls, and following more hormone for weight loss in euthyroid individuals,than 5% weight loss, TSH and FT3 decreased in the thyroid hormone has been used illegally in dietaryobese girls. In another pediatric study, 246 obese supplements marketed for weight loss in severalchildren attending a weight loss program were countries. A recent study from Hong Kong notedfollowed for 1 year [38]. At baseline, serum TSH the presence of illicit thyroid hormone in 20 of 66and FT3 were higher in the obese children than in cases of weight loss products resulting in poisoningnormal-weight controls, but FT4 did not differ. At between 2004 and 2009 [44]. Nine of these patients1 year, there was a significant decrease in TSH and presented with overt thyrotoxicosis, and one hadFT3 in the 49 children who had achieved signifi- thyrotoxic periodic paralysis.cant weight loss, whereas there was no change in Several thyroid hormone analogues are cur-serum TSH in the 197 obese children who did not rently in development. Most of the thyroidlose weight. hormone’s effect on bone and heart are mediated In a prospective study of 11 obese premeno- by a isoforms of the thyroid hormone receptor,pausal women, thyroid function was assessed before whereas effects on the liver, such as lipid lowering,and after 50% excess weight loss was achieved by are mediated primarily by thyroid hormone recep-diet [39]. At baseline, serum TSH was higher than in torb. Selective thyroid hormone receptorb agonists,normal-weight controls, and weight loss was associ- therefore, are appealing as medications for hyper-ated with reductions in serum TSH and FT3. The lipidemia or obesity that might selectively lowerdecline of serum TSH correlated with decreases in lipids or weight without bone or cardiac toxicityserum leptin. In a retrospective study of 258 euthy- [45]. Weight loss has been observed with someroid morbidly obese patients who underwent gastric of these compounds in animal studies. Howeverbanding, thyroid function was ascertained before weight loss with thyroid mimetic treatment hasand up to 24 months after the bariatric surgery not yet been reported in clinical trials [45,46],[40]. Following weight loss, FT3 levels decreased despite improvements in lipid parameters inand FT4 increased, without significant changes in patients treated with the thyroid hormone analogueserum TSH. In a prospective study of 98 premeno- eprotirome [46], and knockout studies suggest thatpausal obese women, thyroid function was studied regulation of basal metabolic rate is more dependentbefore and after 6 months of treatment with sibutr- on thyroid hormone receptora than thyroidamine or orlistat [41]. At 6 months, although hormone receptorb [45]. One recent preliminaryBMI and leptin levels had decreased significantly, study of treatment with 3,5-diiodo-L-thyronine inthere were no significant changes in TSH, FT3, two euthyroid human volunteers did demonstrate aor FT4 values. In another recent prospective significant 4% decrease in body weight without1752-296X ß 2012 Wolters Kluwer Health | Lippincott Williams Wilkins www.co-endocrinology.com 411Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  5. 5. Thyroid 8. Polotsky HN, Brokhin M, Omry G, et al. Iatrogenic hyperthyroidism does not changes in serum FT3, FT4, or TSH; changes in fat promote weight loss or prevent ageing-related increases in body mass in mass were not evaluated [47 ]. thyroid cancer survivors. Clin Endocrinol (Oxf) 2012; 76:582–585. In this retrospective study, iatrogenic hyperthyroidism in thyroid cancer survivors over up to a 5-year follow-up period was associated with weight gain similar, or even greater than that seen in euthyroid population controls. CONCLUSION 9. Celi FS, Zemskova M, Linderman JD, et al. Metabolic effects of liothyronine therapy in hypothyroidism: a randomized, double-blind, crossover trial of The interrelationships between body weight and liothyronine versus levothyroxine. J Clin Endocrinol Metab 2011; 96:3466– 3474. thyroid status are complex. Weight decreases fol- In this blinded cross-over clinical trial, carefully titrated L-T3 therapy was asso- lowing treatment for hypothyroidism. However, ciated with weight loss, whereas L-T4 therapy was not. 10. Buerba R, Roman SA, Sosa JA. Thyroidectomy and parathyroidectomy in following L-T4 treatment for overt hypothyroidism, patients with high body mass index are safe overall: analysis of 26 864 weight loss appears to be modest and mediated patients. Surgery 2011; 150:950–958. 11. Weinreb JT, Yang Y, Braunstein GD. Do patients gain weight after thyroi- primarily by loss of water weight rather than fat. dectomy for thyroid cancer? Thyroid 2011; 21:1339–1342. A single recent study suggests that carefully titrated This observational study found no difference in weight change in thyroid cancer patients following total thyroidectomy compared with euthyroid controls. L-T3 treatment in hypothyroid patients may cause 12. Jonklaas J, Nsouli-Maktabi H. Weight changes in euthyroid patients under- greater weight loss than treatment with L-T4. There going thyroidectomy. Thyroid 2011; 21:1343–1351. This observational study found that patient who had undergone a thyroidectomy in is conflicting evidence about the effects of thyroid- the previous year gained more weight than matched hypothyroid controls who had ectomy on weight. In large population studies, even not undergone thyroid surgery. ´ 13. Dıez JJ, Iglesias P. Relationship between thyrotropin and body mass index in among euthyroid individuals TSH is typically posi- euthyroid subjects. Exp Clin Endocrinol Diabetes 2011; 119:144–150. tively associated with body weight and BMI. Both 14. Soriguer F, Valdes S, Morcillo S, et al. Thyroid hormone levels predict the change in body weight: a prospective study. Eur J Clin Invest 2011; serum TSH and T3 are typically increased in obese 41:1202–1209. compared with lean individuals, an effect likely 15. Svare A, Nilsen TI, Bjøro T, et al. Serum TSH related to measures of body mass: longitudinal data from the HUNT Study, Norway. Clin Endocrinol (Oxf) mediated, at least in part, by leptin. Finally, there 2011; 74:769–775. is no consistent evidence that thyroid hormone In this prospective cohort study, weight gain over 10.5 years of follow-up was associated with increases in serum TSH. treatment induces weight loss in obese euthyroid 16. Prats-Puig A, Sitjar C, Ribot R, et al. Relative hypoadiponectinemia, insulin individuals, but thyroid hormone analogues may resistance, and increased visceral fat in euthyroid prepubertal girls with low- normal serum free thyroxine. Obesity (Silver Spring) 2011. [Epub ahead of eventually be useful for weight loss. print] 17. Alevizaki M, Saltiki K, Voidonikola P, et al. Free thyroxine is an independent Acknowledgements predictor of subcutaneous fat in euthyroid individuals. Eur J Endocrinol 2009; 16:459–465. No funding was received for this work. 18. Lu S, Guan Q, Liu Y, et al. 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