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Serum Ghrelin Levels in Hypothyroid Patients

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Serum Ghrelin Levels in Hypothyroid Patients SERUM GHRELIN LEVELS IN HYPOTHYROID PATIENTS Dissertation submitted to THE TAMILNADU Dr. MGR MEDICAL UNIVERSITY CHENNAI—600032. In partial fulfilment of the requirement for the award of the degree of DOCTOR OF MEDICINE IN BIOCHEMISTRY BRANCH XIII DEPARTMENT OF BIOCHEMISTRY COIMBATORE MEDICAL COLLEGE COIMBATORE-641014. MAY 2020 UNIVERSITY REGISTRATION NO – 201723653 BONAFIDE CERTIFICATE This is to certify that the dissertation entitled “SERUM GHRELIN LEVELS IN HYPOTHYROID PATIENTS” is a bonafide original work done by Dr. P.SUMATHI in partial fulfilment of the requirements of M.D Biochemistry [Branch-XIII] examination of The Tamilnadu Dr.M.G.R Medical University to be held in May 2020. HOD & GUIDE: DEAN: Dr.S.MANIMEKALAI M.D., Dr.B.ASOKAN M.S.,M.Ch., PROFESSOR AND HOD, Coimbatore Medical College & Hospital, Department of Biochemistry, Coimbatore-14. Coimbatore Medical College, Coimbatore-14. DECLARATION I Dr.P.SUMATHI solemnly declare that the dissertation titled “SERUM GHRELIN LEVELS IN HYPOTHYROID PATIENTS” is done by me at Coimbatore Medical College& Hospital, Coimbatore during the period from March 2018- February 2019 under the guidance and supervision of Prof.Dr.S.MANIMEKALAI, M.D., Professor & HOD, Department of Biochemistry, Coimbatore Medical College, Coimbatore600014. This dissertation is submitted to The Tamil Nadu Dr. M.G.R. Medical University towards the partial fulfilment of the requirements for the award of M.D Degree [Branch-XIII] in Biochemistry. Place: Coimbatore. Dr.P.Sumathi, Date: Post Graduate Student, Department of Biochemistry. CERTIFICATE II This is to certify that this dissertation work titled “SERUM GHRELIN LEVELS IN HYPOTHYROID PATIENTS” of the candidate Dr.P.SUMATHI with Registration Number 201723653 for the award of M.D.DEGREE in the branch of BIOCHEMISTRY. I personally verified the urkund.com website for the purpose of plagiarism check. I found that the uploaded thesis file contains from introduction to limitation pages and result shows 15% (FIFTEEN) of plagiarism in the dissertation. Guide & Supervisor sign with seal. ACKNOWLEDGEMENT I express my sincere thanks to the respected Dean Dr.B.ASOKAN,M.S,MCh, for allowing me to undertake this study in our hospital. I am extremely grateful to Prof. Dr.S.MANIMEKALAI M.D., Professor and Head of the Department of biochemistry for permitting me to carry out my study and for her constant encouragement and guidance. I am extremely thankful to Dr. ELANGO, M.S, Professor and Head of the Department, Department of Surgery, for granting permission to obtain blood samples from the patients. I take immense pleasure in expressing my sincere thanks to Associate Professor Dr.A.VEENA JULIETTE M.D., for her constant encouragement and guidance. I personally thank to Prof. Dr.N.DHEEBALAKSHMI M.D., for her valuable opinion & guidance to perform this work. I thank Assistant Professor Dr.G.EZHIL M.D., for her continuous motivation and valuable guidance throughout my work. I whole heartedly thank my parents, my husband & daughters M.S.HARSHINI & M.S.SHRI HARINI, my colleagues, and staff of our Central Lab for their support for this work. I thank Dean& Nodal Officer of the Multidisciplinary Research Unit, of Coimbatore Medical College for allowing me to utilize the ELISA equipment for the analytical process. I owe my sincere thanks to all the patients for their kind co-operation throughout the study. ABBREVIATIONS BMI Body Mass Index HT Hypertension GH Growth Hormone DM Diabetes Mellitus GIT Gastro Intestinal Tract CNS Central Nervous System BBB Blood Brain Barrier IP Intraperitoneal ICV Intracerebroventricular CHO Cholesterol TG Triglycerides LDH Lactate Dehydrogenase CLIA Chemiluminiscence Immune Aassay T3 Tri IodoThyronine T4 Thyroxine TSH Thyroid Stimulating Hormone TRH Thyrotropin Releasing Hormone HPT Hypothalamic-Pituitary-Thyroid axis D1 Deiodinase 1 Dio1 Deiodinase 1 gene D2 Deiodinase 2 Dio2 Deiodinase 2 gene D3 Deiodinase 3 Dio3 Deiodinase 3 gene DIT Di Iodo thyronine MIT Mono Iodo Thyronine GOAT Ghrelin Octo Acyl Transferase NIS Sodium/ Iodide Symporter NPY Neuropeptide Y AgRP Agouti Related Protein GHS-R Growth Hormone Secretogogue Receptor TR Thyroid hormone receptor TPO Ab Thyroid peroxidase antibodies TAb Thyroglobulin Antibodies EGF Epidermal Growth Factor IGF Insulin like Growth Factor AMPK 5- adenosine monophosphate-activated protein kinase α-MSH Alpha-melanocyte-stimulating hormone ARC Arcuate nucleus BDNF Brain-derived neurotrophic factor MC4R Melanocortin 4 receptor MCT8 Monocarboxylate transporter 8 OATP1C1 Organic anion transporting polypeptide 1c1 PVN Paraventricular nucleus POMC Pro-opiomelanocortin rT3 Reverse T3 SF1 Steroidogenic factor-1 UCP1 Uncoupling protein 1 UCP2 Uncoupling protein 2 VMN Ventromedial nucleus. TABLE OF CONTENTS S. No CONTENT PAGE NO 1. INTRODUCTION 1-5 2. AIM & OBJECTIVES 6 3. REVIEW OF LITERATURE 7-48 4. MATERIALS & METHODS 49-58 5. STATISTICAL ANALYSIS 59 6. RESULTS 60-77 7. DISCUSSION 78-81 8. CONCLUSION 82 9. LIMITATIONS OF STUDY 83 10. BIBLIOGRAPHY ANNEXURE A) PROFORMA B) CONSENT FORM 11. C) ETHICAL COMMITTEE APPROVAL CERTIFICATE D) URKUND DIGITAL RECEIPT E) MASTER CHART INTRODUCTION INTRODUCTION HYPOTHYROIDISM Hypothyroidism is the clinical presentation , when thyroid gland is not able to synthesise adequate amount of thyroid hormones, tri- iodothyronine (T3) and thyroxine(T4), to maintain normal blood levels and to the needs of peripheral tissues(1). Primary hypothyroidism is disease in the thyroid gland itself that is unable to produce adequate thyroid hormones. Many patients present with primary hypothyroidism. Permanent Loss or destruction of the thyroid cells, through autoimmune destruction, like Hashimoto disease or irradiation injury, is under Primary Hypothyroidism(1). Hypothyroidism is rarely secondary, caused by disease in the pituitary gland or hypothalamus resulting in inadequate production of thyroid-stimulating hormone (TSH)(2). Transient or progressive loss of hormone biosynthesis is associated with compensatory thyroid gland enlargement. Central or secondary hypothyroidism is caused by inadequate stimulation of a normal thyroid gland, is the result of hypothalamic axis or pituitary axis defects in the TSH molecule(3). Transient or temporary hypothyroidism can be identified as a course of subacute thyroiditis(4). Prevalence of hypothyroidism in India is 11% showed in FIG-1. Global distribution of thyroid disorders are depicted in FIG – 2. 1 FIG – 1- PREVALENCE OF HYPOTHYROIDISM FIG – 2- GLOBAL DISTRIBUTION OF THYROID DISORDERS 99% of hypothyroidism cases are due to Primary hypothyroidism and remaining 1% due to TSH deficiency. Calculation of incidence of hypothyroidism varies depending on the population, geographical area, sex, age etc(5) . Subclinical hypothyroidism is defined as increased level of serum TSH concentration with a normal serum T4 concentration(6). Subclinical hypothyroidism can lead to overt hypothyroidism(7). Clinical manifestations of subclinical hypothyroidism are associated with early or mild stage of Hypothyroidism. The incidence of hypothyroidism is more in women, in the elderly, and in some race and ethnic groups, some geographical areas(8) . Neonatal screening programme is done for congenital hypothyroidism. This identifies hypothyroidism in almost 1 in 3000 newborns(9). The presence of normal or increased thyroid hormone production, but decreased thyroid hormone activity at the tissue level produces clinical signs & symptoms of the disease. These conditions include abnormal peripheral metabolism of thyroid hormone and target tissue resistance to thyroid hormones. Congenital primary hypothyroidism may be the consequence of several inborn defects involving key steps needed for development and function of the thyroid gland and associated with 2 different clinical features. Thyroid dysfunction is associated with changes in body weight, food intake, and energy expenditure(10). 3 GHRELIN Ghrelin is a 28-amino acid acyl peptide mainly produced by the stomach and identified in 1999(11) as a natural ligand of the GH secretagogue receptor type 1a (GHS-R1a). It was originally recognized as the stimulus for the release of growth hormone, with multiple actions in the body. Its best-known function involves energy metabolism. Ghrelin is an orexigenic hormone which regulates energy intake by stimulating the appetite, resulting in adipogenesis (the formation of fat cells) and reduced lipolysis (the breakdown of lipids)(11). Circulating total Ghrelin levels are decreased under conditions of positive energy balance, such as obesity, whereas an increase in total Ghrelin concentrations is observed in negative energy balance states, such as anorexia nervosa or diet-induced weight loss(12). At the hypothalamic level, ghrelin stimulates GH release and regulates appetite and energy balance. Increased levels are seen in catabolic conditions and decreased levels are found in obesity. An inverse correlation between serum ghrelin levels and resting energy expenditure (REE) has been recorded in healthy women. Thyroid disease is associated with changes in appetite, food intake, and Resting Energy Expenditure (REE). Hypothyroid patients gain weight inspite of their decreased appetite. 4 Ghrelin is involved in the regulation of food intake, fat storage and energy balance and it has orexigenic effects in humans in whom it stimulates appetite and increases food intake(13). Previous studies have reported decreased levels of ghrelin in hyperthyroidism. As alterations in body weight and appetite are hallmarks of
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