RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE



RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA

BANGALORE

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

|1. |Name of the Candidate |DR. MADHURA. N. S |

| |and Address |POST GRADUATE. |

| |(in block letters) |DEPARTMENT OF BIOCHEMISTRY. |

| | |ESIC MEDICAL COLLEGE & PGIMSR HOSTEL, ESICMH CAMPUS, RAJAJINAGAR, 3rd BLOCK |

| | |BENGALURU 10 |

|2. |Name of the Institution |ESIC MEDICAL COLLEGE & POST GRADUATE INSTITUTE OF MEDICAL SCIENCE & RESEARCH. |

| | |RAJAJINAGAR, BENGALURU 10 |

|3. |Course of study and subject |M.D BIOCHEMISTRY |

|4. |Date of Admission to course |06/06/2011 |

|5. |Title of the Topic |SIGNIFICANCE OF ANTI THYROPEROXIDASE & ANTI THYROGLOBULIN ANTIBODY TITRES IN PATIENTS WITH |

| | |SUBCLINICAL HYPOTHYROIDISM. |

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| |Brief Resume of the intended work : |

| |6.1 Need for the study : |

| |Studies have shown that ,most of the subclinical hypothyroid patients have an elevated anti thyroperoxidase antibody titre,(Anti TPO antibody) |

| |and anti thyroglobulin antibodies suggesting an auto immune etiology as the most common cause for hypothyroidism.The titre of anti TPO |

| |antibodies is proprtional to the degree of lymphocytic infiltration and inflammation within the thyroid gland. Therefore, subclinical |

| |hypothyroid patients with high titre of anti tpo antibodies are more likely to progress to overt hypothyroidism.1 |

| |Prospective studies of women with subclinical hypothyroidism have shown rates of progression ranging from approximately 3% to 8% per year, |

| |with the higher rates seen in individuals with initial TSH concentrations greater than 10 mU/L and in those with positive TPO-Ab.2 |

| |The study aims to find the undiagnosed subclinical hypothyroid cases, among the middle aged females attending ESI model hospital and to |

| |estimate the anti tpo antibody, anti thyroglobulin antibody titre in them. If significantly high titres are revealed, early treatment can be |

| |started in such patients in order to prevent them from progressing to overt disease. |

| |6.2 Review of literature : |

| |Subclinical hypothyroidism ;By definition, subclinical hypothyroidism refers to biochemical evidence of thyroid hormone difficiency in patients |

| |who have few or no apparent clinical features of hypothyroidism. There are no universally accepted recommendations for the management, the but |

| |most recently published guidelines do not recommend treatment when TSH levels are below 10 m U/L. 2 |

| |Prevalence of subclinical hypothyroidism is found to be 6-8% in women and 3% in men.2 |

| |The term subclinical hypothyroidism was originally used to describe the patient with a low-normal freeT4 but a slightly elevated serum TSH |

| |level. Other terms for this condition are mild hypothyroidism, early thyroid failure, preclinical hypothyroidism , and decreased thyroid reserve|

| |. |

| |The TSH elevation in such patients is modest, with values typically between 4 and 15  mU/L (normal:0.5-5m IU/L), although those patients with a|

| |TSH greater than 10 mU/L more often have a reduced T4 and may have some hypothyroid symptoms. The risk of progression from subclinical to |

| |overt hypothyroidism (i.e., with elevated serum TSH and reduced serum T4 concentrations) is most closely related to the magnitude of serum TSH |

| |elevation and the presence of TPO-Ab. Although most patients progress slowly to overt hypothyroidism , rapid progression over weeks to months |

| |has been reported. Factors that may predispose to rapid progression include elderly age, high levels of TPO-Ab, intercurrent systemic infection |

| |or inflammation, iodinated contrast agents, and medications such as amiodarone and lithium.3 |

| |Autoimmune hypothyroidism is the most common cause of hypothyroidism in iodine-sufficient areas of the world. The vast majority of cases of |

| |autoimmune hypothyroidism are due to Hashimoto thyroiditis. Circulating autoantibodies, including anti-microsomal, anti-thyroid peroxidase, and |

| |anti-thyroglobulin antibodies, are found in this disorder, and the thyroid is typically enlarged (goitrous).4 |

| |Circulating antithyroid antibodies, specifically antimicrosomal (AMA) and antithyroglobulin(ATA) antibodies, are usually present in patients |

| |with autoimmune thyroid disease. Since the introduction of immunoassay techniques, the term antithyroperoxidase (anti-TPO) has become |

| |interchangeable with AMA. AMAs are detectable in more than 90% of patients with chronic autoimmune thyroid disease; nearly 100% of patients with|

| |Hashimoto's thyroiditis and more than 80% of patients with Graves’ disease have positive titers. Although ATAs are more specific than AMAs, they|

| |are less sensitive, and they are not as useful in the detection of autoimmune thyroid disease.5 |

| |Thyroid peroxidase or thyroperoxidase (TPO) is an enzyme expressed mainly in the thyroid that liberates iodine for addition onto tyrosine |

| |residues on thyroglobulin for the production of thyroxine (T4) or triiodothyronine (T3), thyroid hormones. 6 |

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| |Thyroid peroxidase is a frequent epitope of autoantibodies in autoimmune thyroid disease, TPO is the key thyroid enzyme catalyzing both the |

| |iodination and coupling reaction for the synthesis of |

| |thyroid hormone. It is membrane bound and found in the cytoplasm and in high concentration on the apical microvillar surface of thyrocytes. |

| |Autoantibodies to thyroid peroxidase (TPOAb) are produced within the body thus leading to thyroid dysfunction.6 |

| | TSH and the prevalence of antithyroid antibodies are greater in females, increase with age. TgAb alone in the absence of TPOAb is not |

| |significantly associated with thyroid disease. The lower prevalence of thyroid antibodies and lower TSH concentrations need more research to |

| |relate these findings to clinical status. The high prevalence of elevated serum TSH and antithyroid antibodies, especially in women and the |

| |elderly, suggests that thyroid disease should be considered during routine evaluation and should be followed by appropriate detection and |

| |treatment.7 |

| |A study by hollowel et al, 2002 on “serum tsh, t4, and thyroid antibodies in US population” concluded that there is high prevalence of elevated |

| |tsh and anti TPO antibodies in US population especially in adult females suggesting that all asymptomatic adult females should be screened for |

| |routine evaluation of thyroid function7. |

| |In a study by shruthi Mohanty et al, 2006 (T3), (T4), (TSH) and anti thyroid peroxidase antibodies (anti-TPO) were estimated on fasting blood |

| |samples from 99 patients where 61% patients had subclinical hypothyroidism. 45 of the 61 subclinical hypothyroid patients had elevated anti-TPO |

| |levels (73%) suggesting an autoimmune etiology as most common cause for subclinical thyroid dysfunction. 8 |

| |Anna Lucar et al, conducted a cross-sectional study in spain, where its shown that Undiagnosed thyroid dysfunction was 5.3% (hypothyroidism |

| |3.8%; 56.66% of these subjects were women). Thyroperoxidase antibodies were positive in 2.4% of men and 9.4%in of women and thyroglobulin |

| |antibodies, in 1.3% of men and 3.8% of women.9 |

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| |Rebeca Abraham et al, 2009 conducted a cross sectional study in puducherry where Of the total 505 women examined 15.8% had thyroid dysfunction |

| |and 84.2% were euthyroid. 11.5% were hypothyroid (9.5% sub-clinical) and 1.8% hyperthyroid (1.2% clinical). 19% of women over 60 years had |

| |elevated TSH above 4.5 μIU/m,suggesting that Hypothyroidism particularly sub-clinical hypothyroidism is predominantly present amongst women in |

| |this iodine sufficient region.10 |

| |Hossein Gharib et al, 2005 concluded that the measurement of anti-TPO antibodies is a valuable adjunct in the evaluation of patients with |

| |subclinical hypothyroidism, as it “predicts a higher risk of developing overt hypothyroidism (4.3% per year vs. 2.1% per year in |

| |antibody-negative individuals). 11 |

| |Atish chouhan et al, 2010 conducted a study in individuals who are living around S.R.M. Medical College, Kattankulathur where it was found that|

| |in some individuals who were supposed to be normal in clinical condition also had the abnormal values in thyroid function indicates there is a |

| |possibility of a subclinical hypothyroidism.12 |

| |6.3 Objectives of the study : |

| |To estimate the serum levels TSH , anti TPO antibodies and antithyroglobulin antibodies in cases and controls.. |

| |To compare the serum levels of antithyroid antibodies in cases and controls. |

| |All the above objectives will be carried out in patients attending medicine opd, ESIC MODEL HOSPITAL.,Rajaji nagar, Bangalore. |

| |Material and methods : |

| |7.1 Source of data : Females patients attending medicine opd, at ESIC MH, Rajajinagar, Bangalore, in the time period of one year from dec |

| |2011 to dec 2012. |

| | |

| |Inclusion criteria : |

| |Female patients in the age group of 18 to 60 years of age, with marginally elevated TSH(4m IU/L-10m IU/L) and normal T3 (120-190 ng/dl), T4 |

| |(5-12 µg/dl) will be included in the study. |

| |Age and sex matched euthyroid patients will be taken as controls of the study. |

| |Exclusion criteria: |

| |•Females in gestational or postpartum period |

| |• Thyroid destruction (from radioactive iodine or surgery) |

| |•Medications causing thyroid dysfunction like amiodarone, lithium, antithyroid drugs etc. |

| |•known cases of overt hypothyroidism or hyperthyroidism. |

| |. Other causes of TSH elevation like Impaired renal function, following withdrawl of thyroid hormone therapy. |

| |7.2 METHOD OF COLLECTION OF DATA: |

| |Sample size: 100 patients(50 cases and 50 controls).50 consecutive subclinical hypothyroid patients referred from biochemical evaluation. |

| |Sample collection: .After taking informed consent, about 5ml of venous Blood sample will be collected aseptically. Blood is allowed to clot; |

| |samples will be centrifuged at 2000 rpm(revolution per minute) for 10 minute at room temperature. Serum is separated and stored at -20°C until |

| |the analysis, to minimize non-specific variability of all parameters. |

| |LIST OF INVESTIGATIONS |

| |1. Lipid profile, RBS, and Renal function tests analysed by standard clinical chemistry |

| |methods by autoanalyser. |

| |2. Thyroid function tests by chemiluminescent immunoassay.13 |

| |3. Anti-TPO antibody and Anti-thyroglobulin antibody estimation by chemiluminescent |

| |immunoassay.13 |

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| |Statistical analysis : |

| |The measured parameters will be expressed as Mean ± Standard deviation. The data generated will be compared using student ‘t’ test / ANOVA test |

| |at 5% level of significance. Correlations between the parameters will be done using Pearson’s correlation coefficient test at 5% level of |

| |significance. |

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| |7.3 Does the study require any investigations or interventions to be |

| |conducted on patients or other humans or animals? |

| |YES. Our study invovles human population, Informed consent will be obtained as per the proforma. Routine biochemical investigation, anti TPO |

| |will be done. |

| |7.4 Has ethical clearance been obtained from your institution in case |

| |of 7.3? |

| |YES |

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| |8. REFERENCES: |

| |Parmar MS, Jones NT, Topless DJ, Eastman CJ . Diagnosis and management of hyperthyroidism and hypothyroidism. Med J Aust . 2004; 180 (10): |

| |541-542. |

| |Fauci, Braunwald, Kasper, Hauser, Longo, Jameson et al. Harrisons principles of internal medicine. 17th edition. Mc Graw Hill.2008; vol |

| |2;2232-33. |

| |Melmed S, Kronberg HM, Polosky KS, Larsen PR. Williams textbook of Endocrinology 11th edition. Philadelphia. Elsevier Saunders .2008;400 |

| |Kumar, Abbas, Fausto. Robbins and Cotran Pathological Basis of Disease, Professional edition, 7th edition. Philadelphia. Saunders Elsevier. |

| |2005;1169 |

| |Flint, Harker LA, Haughey BH, Richardson MA, Robbins KJ. Cummings otolaryngology: Head and Neck Surgery, 5th edition. Philadelphia. Mosby |

| |Elsevier. 2010;vol3;2669. |

| |McLachlan SM, Rapoport B. Autoimmune response to the thyroid in humans: thyroid peroxidase--the common autoantigenic denominato. Int. Rev. |

| |Immunol. 19 (6): 587–618. |

| |Hollowell JG, Staehling NW, Flanders WD. Serum TSH, T4 and thyroid |

| |antibodies in the United States population (1988-1994): National Health and |

| |Nutrition Survey . J Clin Endocrinol Metab; 2002; 87: 486-488. |

| |Shruthi Mohanty,Amruthlal W, Reddy GC, Kusumanjali G, Sabapathy AS, Pragna R. .Diagnostic stratergies for Subclinical hypothyroidism |

| |;IJCB:2006:23(3):279-82 |

| |Anna lucar ,Teresa JM,,Ana C, Conxa C,Roser C, Caceres M, Maria E .Undiagnosed thyroid dysfunction,&thyroid antibodies in Mediterranean |

| |population: Endocrine journal:2010:38(3):391-96. |

| |Rebecca Abraham, Murugan SV ,Vanthen PP ,Sen SK. Thyroid disorders in women of puduchery.IJCB:2009:24(1):52-5. |

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| |Gharib H,Tuttle RM, Baskin HJ,Fish LH,Peter A, Mc Dermatt MT. Subclinical thyroid dysfunction. JCME 2005:90(1):581-85. |

| |Chavan A, Kumar M, Prasad D, Sundaresan S , Thangapannerselvem T A Study on |

| |Anti-Thyroid Peroxidase, Thyroxine,Tri-Iodothyronine TSHSubclinicalHypothyroidism. |

| |International Journal of ChemTech Research Jan2010:2(1):219-223. |

| |Walkar KT. Introduction: An approach to immune assay. Clin chem 1977;23:384 |

| 9 |Signature of candidate | |

|10 |Remarks of the guide | |

|11 |Name & Designation of (in block letters) |DR.V. VIJAYA KUMARI. |

| |11.1 Guide |ASSOCIATE PROFFESSOR |

| | |DEPARTMENT OF BIOCHEMISTRY |

| |11.2 Signature |ESI MEDICAL COLLEGE &PGIMSR , |

| | |RAJAJI NAGAR ,BENGALURU.10. |

| |11.3 Co-Guide I | |

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| |11.4 Signature |DR. T. ANIL KUMAR |

| | |PROF AND HOD |

| |11.5 Head of department |DEPT OF GENERAL MEDICINE |

| | |ESI MEDICAL COLLEGE& PGIMSR, RAJAJINAGAR |

| | |BENGALURU.10 |

| |11.6 Signature | |

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| | | |

| | |DR .K.PRATHIBHA |

| | |PROF. AND HOD, |

| | |DEPARTMENT OF BIOCHEMISTRY, |

| | |ESI MEDICAL COLLEGE&PGIMSR,RAJAJINAGAR BANGALURU.10. |

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|12 |12.1. Remarks of the |DR.B. RAJEEV SHETTY |

| |Dean & Principal |THE DEAN. |

| | |ESI MEDICAL COLLEGE& PGIMSR,RAJAJINAGAR BENGALURU.10. |

| | | |

| |12.2. Signature | |

Proforma

Name

Age sex

Address

Occupation Religion Date of admission

Chief complaints

History of present illness

Past history

Personal history

Family history

Treatment history

General physical examination PR BP TEMP RR

Examination of neck for any thyroid swelling

Systemic examination

Central Nervous System Examination

C.V.S Examination

Respiratory Examination

Per abdominal Examination

INFORMED CONSENT FORM

TITLE OF THE PROJECT: Significance of antithyroperoxidase antibody and

Antithyroglobulin antibody titres in patients with subclinical hypothyroidism

PURPOSE OF RESEARCH& BENEFITS:

I have been informed that the present study will not harm me in any form, instead I will be helped by the study in terms of diagnosis& treatment. The future generation and other patients will also be helped by the study.

PROCEDURE

I understand that after having obtained a detailed clinical history and thorough clinical examination,5ml of venous blood sample will be collected under aseptic precautions and processed for determination of Lipid profile, RBS,RFT’S, TFT’S, Anti tpo antibody &antiTGantibody titres.If any discomfort during the withdrawl, it would be minimal.

.CONFIDENTIALITY:

I understand that the this study will become a part of hospital records and will be subject to the confidentiality.If the data are used for publication, no name will be used and photographs will be used with special written permission.

REFUSAL FOR WITHDRAWAL OF PARTICIPATION:

I understand that my participation is voluntary and that I may refuse to participate or withdraw consent and discontinue participation in the study at any time.

INJURY STATEMENT :

I understand that in the unlikely event of injury to me resulting directly from my participation in this study, if such injury were reported promptly, the appropriate treatment would be available to me

PARTICIPANT CONSENT STATEMENT:

I confirm that Dr Madhura NS , PG in DEPT of Biochemistry. has explained to me all the above in detail in my own language and I understand the same. Therefore I agree to give consent to participate as a subject in this research project.

__________________________ ________________________

(Participant) Date

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