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Home , Thyroid function tests

Biochemistry Kumawat Manjulata et al. / JPBMS, 2012, 21 (01)

Available online at www.jpbms.info ISSN NO- 2230 – 7885 CODEN JPBSCT Original researchJPBMS article NLM Title: J Pharm Biomed Sci.

JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL SCIENCES

Is There Receptor Resistance In ?

Kiran Chugh1, Sandeep Goyal2, Vijay shankar1,* Manjulata Kumawat1, S.N. Chugh2, Manjri Goyal2. 1Department of Biochemistry, Pt. B. D. Sharma University of Health Sciences, Rohtak, Haryana, India. 2Department of Medicine, Pt. B. D. Sharma University of Health Sciences, Rohtak, Haryana, India. Abstract: Background and Objectives: is the name given to a syndrome that is seen more often in people who are overweight or obese, and who have specific conditions that increase the risk of disease, , stroke, and other health problems. Metabolic syndrome is diagnosed when three out of the following five risk factors are evident. Researchers have now found that even subtle changes in thyroid function increase the risk for metabolic syndrome. We evaluated the thyroid function tests in obesity to explore the possibility of thyroid receptor resistance. Methods: the study was a cross-sectional study. It included 50 obese subjects with Body Mass Index (BMI) > 30 kg/m2 as 2 cases (group I) and 25 individuals with BMI < 25 kg/m as controls (group II). T3 (Triiodothyronin), T4 (Thyroxine), TSH (Thyroid stimulating ) levels were measured as indicator of thyroid functions. Blood sugar and levels were measured. To define insulin resistance, Homeostasis model for insulin resistance (HOMA IR) was calculated in both groups and the HOMA IR value obtained in group II individuals served as reference mark. Based on the HOMA IR, group I subjects were divided into insulin resistant (subgroup IA) and insulin nonresistant (subgroup IB) individuals. Thyroid function tests were compared in both subgroups. Results: T3 and T4 levels were comparable whereas there was significant difference in TSH levels in insulin resistant (subgroup IA) and insulin nonresistant (subgroup IB) individuals. Conclusion: Raised TSH in insulin resistant obese persons independent of lowered T3 and T4 suggest it to be a part of insulin resistant state in obesity.

Keywords: Obesity, Body mass index (BMI), Thyroid function tests, Insulin resistance, Homeostasis model assessment for insulin resistance (HOMA IR), Thyroid receptor resistance.

Introduction: insulin resistance due to defect in post receptor signal Obesity (BMI > 30 kg/m2) has become a major health transduction in target tissue, a similar mechanism of hazard globally. National health and Nutrition Examination thyroid receptor resistance might be operating in obese [3] surveys (NHANES) revealed an increase in prevalence of persons . Thus, in order to explore the possibility of obesity from 14.5% to 30.5% over a period of two decades thyroid receptor resistance to TSH, the present study was [1]. Obesity occurs due to increased energy intake, designed to find alterations in thyroid functions in obese decreased energy expenditure or a combination of both, insulin resistant and insulin non-resistant individuals [10] thus leading to positive energy balance. Thyroid (insulin resistance defined by HOMA-model) . up regulate metabolic pathways relevant to resting energy expenditure, hence, obesity and thyroid functions are often Materials and Methods: correlated. On one hand, obesity per se causes alterations Study design in thyroid function i.e. increased thyroid hormone levels [2], The study was carried out in 50 obese persons with BMI > [3-5] 2 increased TSH with no effect on T3 and T4 or increase in 30 kg/m (group I) enrolled through the outpatient [6- 8] TSH and T3 with no effect on T4 ; on the other hand, department of medicine of Pt. B. D. Sharma PGIMS, Rohtak. 2 subclinical (increased TSH and normal T3, 25 non obese persons with BMI < 25 kg/m were taken as T4), as a result of slow can lead to the obesity controls (group II). We excluded the subjects with history [9]. It is still not clear whether these alterations in thyroid of thyroid diseases or radioiodine treatment, antithyroid functions are a cause or consequence of obesity. treatment, thyroid autoantibody positive subjects, pregnant women, person with diabetes or having blood One fact is clear that clinicians often interpret increased sugar levels suggestive of impaired fasting glucose or TSH levels with normal thyroid hormone levels in obese impaired glucose tolerance. All patients gave written persons as an evidence of subclinical hypothyroidism and consent and the institutional review board at the prescribe thyroxine replacement therapy to reinforce University of Health Sciences approved the study protocol. euthyroid status which already exists. It has also been noted that the unnecessary use of thyroxine replacement Anthropometric parameters, thyroid function tests, can lead to its toxicity. The mechanism of normal levels of blood glucose and serum insulin levels T3, T4 with increased TSH in obesity is not defined, but it Body weight (kg.) and height (meter) were measured has been hypothesised that obesity is associated with using standardized techniques and equipment. BMI was

1 Journal of Pharmaceutical and Biomedical Sciences ©(JPBMS), Vol. 21, Issue 21 Biochemistry Kumawat Manjulata et al. / JPBMS, 2012, 21 (01) calculated as weight divided by squared height (kg/m2). Table I.BMI and Thyroid function tests in both groups Venous blood samples were taken after 12 hours of fasting Parameters Group I Group II p value and were separated and frozen at -8° C until analysis. BMI 33.17 + 3.73 23.03 + 2.47 < 0.0001 Serum levels of TSH (reference range. 0.17 - 4.05 µIU/ml), T3 (ng/dl) 116.58 + 25.37 123.7 + 18.44 0.22 T3 (. 70-200 ng/dl), T4 (reference range. T4 (µg/dl) 7.75 + 1.28 7.54 + 1.37 0.52 5.5-13.5 µg/dl) were measured as indicators of thyroid TSH (µIU/ml) 5.70 + 1.6 2.21 + 0.87 < 0.0001 function using I-125 gamma counter (IC 4702A, Electronics Values are expressed as mean + S.D. corporation of India, India) with radio immunoassay kits (IRMAK 9, RIAK 4/4A, RIAK 5/5A respectively; Board of Thyroid function tests in insulin resistant and insulin radiation and isotope technology, Navi Mumbai, India). nonresistant obese individuals Serum insulin levels (reference range. 1-30 mU/L) were Group I individuals were divided into insulin resistant and also measured by radio immunoassay kit (RIAK 1, Board of insulin nonresistant obese persons by applying the radiation and isotope technology, Navi Mumbai, India). reference HOMA IR value. 34 obese persons were found to Blood sugar levels (reference range. 60-100 mg/dl) were be insulin resistant (subgroup IA) as compared to 16 estimated by glucose oxidase-peroxidase (GOD-POD) insulin nonresistant obese individuals (subgroup IB). method using glucose analyzer (Techno 168, Logotech Thyroid functions were performed in both subgroups. T India Pvt. Ltd., India). 3 levels were 112.32 + 25.76 ng/dl in subgroup IA and

125.65 + 22.87 ng/dl in subgroup IB and the difference HOMA IR was not significant (fig 1a, p = 0.08). In both subgroups, T To define the insulin resistance, homeostasis model 4 levels were 7.68 + 1.30 µg/dl, 7.90 + 1.21 µg/dl assessment for insulin resistance (HOMA IR) was respectively and the difference was non significant (fig. 1b, calculated by the formula [10]: p = 0.06). TSH levels were 6.08 +1.57 µIU/ml in subgroup

HOMA IR = Fasting blood glucose (mg%) x fasting serum insulin levels (mU/L) IA obese individuals as compared to 4.89 + 1.36 µIU/ml in 405 subgroup IB obese individuals and the difference was statistically significant (fig. 1c, p < 0.01) as displayed in Statistical analysis: table II. The data were analyzed using SPSS software (version 12.0 for windows, SPSS, Inc., Chicago, Illinois). Statistical significance was calculated by Student‘t’ test. Unpaired‘t’ test was used for intergroup comparison. Paired’ test was used for comparison within the group. p value was calculated for Statistical significance. p value < 0.05 was taken as significant. Data were expressed as mean + S.D.

Results: General characteristics of the subjects in both groups The subjects in both groups were between 20-65 years of age. The mean age in group I and group II individuals was 38.24 + 9.17 years and 34.16 + 11.61 years respectively. Female to male ratio (sex ratio) was 3: 2 in both groups.

Comparison of thyroid functions in obese (group I) and control (group II) subjects Fig.1a - T3 levels in subgroups IA and IB 2 The mean BMI was 33.17 + 3.73 kg/m in group I and 23.03 + 2.47 kg/m2 in group II subjects (p < 0.0001) as depicted in table I. Thyroid function tests were done in both groups. The meanT3 levels were comparable in both the groups (116.58 + 25.37 vs. 123.7 + 18.44 ng/dl; p = 0.22). Similarly the difference in meanT4 levels was also nonsignificant in both groups (7.75 + 1.28 vs. 7.54 + 1.37 µg/dl; p = 0.52). Mean TSH levels in Group I individuals were 5.70 + 1.6 µIU/ml as compared to 2.21 + 0.87 µIU/ml in group II and the difference was statistically significant (p < 0.0001) as shown in table I.

HOMA IR HOMA IR (homeostasis model assessment for insulin resistance) was calculated in both groups. The standardized value of HOMA IR, (mean + 2 SD = 6.4) obtained in group II was taken as reference value to define the insulin resistance. The mean HOMA IR was 7.26 + 2.26 in group I and 3.82 + 1.31 in group II individuals and the difference was significant (p < 0.001). Fig.1b -T4 levels in subgroups IA and IB

2 Journal of Pharmaceutical and Biomedical Sciences© (JPBMS), Vol. 21, Issue 21 Biochemistry Kumawat Manjulata et al. / JPBMS, 2012, 21 (01)

Table II. Thyroid function tests in subgroups IA and IB + 25.76 vs. 125.65 + 22.87 ng/dl) and T4 (7.68 + 1.30 vs. Thyroid function Subgroup IA Subgroup IB p value 7.90 + 1.21 µg/dl) were comparable in both IA and IB but tests TSH levels in IA (6.08 +1.57 µIU/ml) were significantly T3 (ng/dl) 112.32 + 25.76 125.65 + 0.08 22.87 higher than in IB (4.89 + 1.36 µIU/ml). Our finding suggest T4 (µg/dl) 7.68 + 1.30 7.90 + 1.21 0.06 that insulin resistant obese persons had higher TSH levels TSH (µIU/ml) 6.08 +1.57 4.89 + 1.36 < 0.01 as compared to noninsulin resistant persons but T3 and T4 Values are expressed as mean + S.D. levels were comparable and normal in both subgroups. BMI, body mass index; T3, Triiodothyronin; T4, Thyroxine; TSH, Thyroid Raised TSH thus could be hypothesized to be a metabolic stimulating hormone consequence of obesity rather than subclinical Discussion: hypothyroidism. From our findings, it can be hypothesized that raised TSH Obesity, an important component of metabolic syndrome, levels in obese persons with insulin resistance could be can be associated with endocrinal and nonendocrinal due to association of thyroid receptor resistance to TSH disorders and has widespread consequences. Alterations in similar to insulin resistance. The normal levels of T and T thyroid functions, though well known yet are not 3 4 support this hypothesis. The stimulus for rise in TSH could recognized clinically and there is inconsistency in the also be due to hormones secreted by . Since thyroid functions in obesity. Rise in TSH with normal T 3 we did not estimate these hormones (, , and T is mostly reported [3-5], but rise in TSH with 4 etc) in our study, thus are not able to comment alteration in T without any effect on T [6-8] or increased 3 4 on the effect of these hormones on thyroid function tests. thyroid hormone levels [2] also have been described in To conclude, it is suggested that these findings are obesity. These disturbances in the thyroid function do not preliminary and require evaluation on a large scale with have any physiological basis because it cannot be explained inclusion of various hormones elaborated by adipose by the feedback mechanism. By this study, we tried to tissue. explore the possibility of thyroid receptor résistance akin to insulin resistance in obesity and made interesting observations. Acknowledgements: We are indebted to the staff of the Department of 75 individuals based on BMI were divided into two groups. Biochemistry and medicine for their technical Group I had 50 obese subjects with BMI >30 kg/m2 while assistance. All authors contributed to the skilful editing 25 nonobese individuals with BMI < 25 kg/m2 constituted of the manuscript and interpretation of results. No group II. Patients with prior history of , financial aid or any other type of grant was accepted for history of antithyroid treatment, with positive antithyroid this work. antibody or with diabetes/impaired glucose tolerance and pregnancy were excluded. All the subjects were subjected References: to thyroid hormone assay and insulin level estimation. 1. Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Homeostasis model assessment for insulin resistance Overweight and obesity in United States: Prevalence (HOMA IR) was calculated. and trends, 1960-1994. Int J Obest 1998; 22: 39-47. The persons in both groups were made comparable with 2. Michalaki MA, Vagenakis AG,. Leonardou AS, Argentou regards to age, sex but had significant difference with MN, Habeos IG, Makri MG. Thyroid Function in Humans regards to BMI (p < 0.0001) and waist hip ratio (p < 0.03) with Morbid Obesity. Thyroid; 2006; 16 (1):73- 8. so as to have a good contrast. 3. Bastemir M, Akin F, Alkis E, Kaptanoglu B. Obesity is The mean levels of T3 (116.58 + 25.37 ng/dl) and T4 (7.75 associated with increased serum TSH level, + 1.28 µg/dl) in group I and mean T3 levels (123.7 + 18.44 independent of thyroid function. Swiss Med weekly ng/dl) and T4 (7.54 + 1.37 µg/dl) in group II were 2007; 137: 431-4. comparable, however the mean levels of TSH in group I 4. Tagliaferri M, Berselli ME, Calo`G, Minocci A, Savia G, (5.70 + 1.60 µIU/ml) were significantly higher than in Petroni ML et al. Subclinical Hypothyroidism in Obese group II (2.21 + 0.87 µIU/ml). The raised TSH levels with Patients: Relation to Resting Energy Expenditure, normal T3 and T4 could not be explained on the basis of Serum Leptin, Body Composition, and . feedback system. These findings also do not explain the Obesity research 2001; 9(3):16-2019. state of subclinical hypothyroidism as all these patients 5. Kundsen N, Lamberg P, Rasmussen LB, Bulow I, Perrild were antithyroid peroxidase antibody negative. H, Ovessen L et al. Small differences in thyroid function Keeping in mind that obesity is associated with insulin may be important for body mass index and the resistance with hyperinsulinaemia as a metabolic occurrence of obesity in the population. J Clin Endo & consequence [11]; it is possible that these patients might Metab 2005; 90: 4019-24. have thyroid receptor resistance resulting in persistent 6. Stichel H. Allemand D, Gruter A. Thyroid function and elevated TSH levels. The stimulus for increased TSH could obesity in children and adolescents. 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Corresponding Author:- Dr. Manjulata Kumawat House No. 22/ 8FM, Medical Campus, Rohtak, Haryana. Contact no. 0931523899

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