Autoimmune thyroiditis and shift

work

By:Abhishek Dave

MPH(Epidemiology)1st yearhttp://www.webmd.com/women/picture-of-the-thyroid

Autoimmune diseases (AD)

Immune system attacks self antigens³ Can affect any part, organ of the body Causes unknown, some genetic and environmental³ Includes 24 autoimmune diseases(NIH) More diseases falling into AD criteria 80-100 AD prevailing as per AARDA Differs among region, age and gender³

http://www.mult-sclerosis.org/news/Nov2001/FullTextTowardsAUnifyingConceptOfAutoimmuneDiseases.html

Autoimmune Disease burden in USA

At least 23 million people in USA(~8%) have autoimmune diseases¹ Numbers greater than cancer patients(9 million), heart patients(22

million) In top 10 mortality causes in adult women before 65 years of age³ Affects everyone but have female predilection¹ 78% of total affected are women¹

Hashimoto’s Thyroiditis AD affecting Thyroid Gland T cell mediated destruction² Heredity and environmental causes² High iodine, Selenium def. , radiation, infection⁵ Smoking⁶, Post pregnancy ⁷ Male: Female is 8:1 to 10:1 (AARDA)

Immunogenicity of disease

http://www.jautoimdis.com/content/2/1/1/figure/F1

Clinical Features of HT

Weight gain most common symptom³⁵ Sign: enlargement of thyroid gland Diagnosis³⁵: Clinically, Thyroid Tests T4,T3 Anti TPO, Tg antibodies Ultrasonography

Treatment : Life long Thyroid hormone replacement³⁵ Surgery as per condition ³⁵

Enlarged thyroid gland

Histopathology of Hashimoto’s Thyroiditis

Inflammatory cells

http://health-fts.blogspot.com/2012/03/thyroiditis.html

http://www.mylot.com/image/751452/goitre-goitre

Shift work and Hashimoto’s Thyroiditis??

Shift work : including day, evening and night shifts A large number of population work in shifts(~15 million)

They are at risk of many diseases:

Shift work

Stress

Autoimmune Thyroiditishttp://kaleidoscope.cultural-china.com/en/7Kaleidoscope10994.html

http://www.cartoonwork.com/workplace_g52-biological_clock_p515.html

http://www.occup-med.com/content/1/1/25/figure/F4?highres=y

Studies on shift work and multiple disorders

Different studies from early 1980’s to 2014 showed shift work is related to diseases SHIFT WORK

Lung cancer¹¹ ovarian ca.¹² Multiple sclerosis¹³ Diabetes Mellitus¹⁴ breast cancer endometrial ca.¹⁰

https://www.mja.com.au/sites/default/files/issues/199_08_211013/raj10561_fm-1.jpg

Causal Pathway: Night work and Immune dysregulation melatonin- sleep circadian rhythm ³⁶ Immune system regulation¹⁵⁻¹⁷

Melatonin decreases pro inflammatory cytokines: interleukin-2, interferon-γ & TNF-α¹⁹ These cytokines are important Mediator in autoimmune thyroiditis¹⁹

http://www.sleepdisordersguide.com/topics/biological-clock.html

http://www.afsafund.org/research_1996.html

http://www.photobiology.com/v1/maestroni2/

Studies Supporting melatonin hypothesis in various autoimmune disease

Multiple Sclerosis²²⁻²³ Alzheimer’s Disease²⁴⁻²⁵ Systemic Lupus Erythematous²⁶ Diabetes Mellitus type 1 ²⁷ Inflammatory Bowel Disease²⁸

https://www.mdpi.com/1422-0067/14/6/11742/htm

Research question: Can shift work for long periods be a cause of Hashimoto’s thyroiditis in female nurses?

Hypothesis: Shift work for long periods can be a cause of Hashimoto’s Thyroiditis in female nurses.

Null Hypothesis: There is no association between working in shifts and Hashimoto’s Thyroiditis in female nurses.

Why only female nurses for Hashimoto’s Thyroiditis?

• 78% women affected overall in autoimmune diseases¹• 10:1 male : female ratio for Hashimoto³• Females most common in nursing profession than

other professions• 30% work in shifts

Research Study

Study Design Type of study: Case-control study Long latency period(~7 years), not a common disease Location of study: USA Selection of Participants: Nurses Health Study I, II and III NHS I- Dr. Frank Speizer NHS II- Dr. Walter Willett , NIH NHS III- Drs. Walter Willett, Janet Rich-Edwards, Stacey Missmer, and Jorge Chavarro (Channing lab and Harvard SPH) Most recently(2009) 90% of 238,000 NP participated from NHS I and II and 100,000 are being recruited in NHS III We have 214,000 subject eligible as per 2011 questionnaire survey

Identification of cases and controls

Questionnaire from NHS I,II,III Cases: one who marked yes in hypothyroidism Controls: who marked no in that option

Exposure: From the questionnaire shown below Number of nights/week or month

Sample Questionnaire from NHS II

What is exposure and its criteria?

Exposure: Shift work Defined as at least one Night shift (>8 hours) per week in addition to standard day shifts

Exposure: Shift work other than day work of 8-5 At least one evening or night shift At least one night shift per week At least 8 hours per night shift

Outcome

Outcome: Positive disease status of Hashimoto’s Thyroiditis

Outcome criteria: Clinically examined hypothyroid³³ Serological tests: TSH, T4, T3 hormone level³³ Anti Thyroglobulin and Thyroperoxidase antibodies

Inclusion and exclusion criteria of subjects

Inclusion: 1.Female nurses working >10 years 2. Living in USA since that period 3. Willing to participate in study 4. Who has personal/family history of - Autoimmune diseases

Exclusion: 1. Female nurses working <10 years 2. Not living in USA from that period 3. Who are not willing to participate 4. Pregnant women: Due to safety concerns on fetus 5. Cases diagnosed before doing the shift work 6. Taking medication which can effect thyroid gland function

Design Phase of Study Eligible participants are approached Consent taken, study explained Questionnaire formed The data gathered from these forms Some general data taken from NHS questionnaire Diagnostic tests will be run to find true cases and controls

Age, geographical distribution Number of pregnancies⁸ smoking, drinking alcohol Radiation⁸ Other autoimmune disease

Controlling the confounding

Age: MATCHING in design phase

Other confounders: STRATIFIED ANALYSIS in analysis phase

Confounders

Information bias: Retrospective study Difficulty to recall the exposure

1. Non differential 2. Differential

type II error type I error Misclassification of exposure

Decreasing the bias Looking into the schedule sheets of nurses, managed by their employers or hospitals

Bias

a b c d

Hashimoto’s Thyroiditis Yes No

No

Yes

Shif

t w

ork

a+bc+d

a+c

b+d

N

Data Plotting

Data Analysis

Example of multiple logistic regression

Measure of frequency: cannot do in case control

But can measure odds of exposure

Measure of association: (Exposure)Odds Ratio

Odds ratio = Stratified Analysis or Multiple Logistic Regression to control confounding

a x db x c

Characteristics

Case

Control

Unadju-sted OR

Adjus-ted OR

Shift work

Day work

Age

No. of pregnanciesF/H of autoimmune disease (AD)Smoking

Drinking alcohol

Radiation

Other AD +

Limitations: 1. Disease risk can not be measured directly, no incidence/

prevalence rate Only odds of exposure is measured2. Can not confirm temporality3. Possibility of misclassification of exposure4. Misclassification of outcome

Strengths:

1. Useful for disease with long latency period2. Quicker, less expensive and smaller3. Can measure multiple variable at a time

Limitation & strengths

How will this study enlighten our knowledge? Identifying association b/w shift work and Hashimoto’s thyroiditis Can affect 20 million people around USA Multiple variables at a single time New labor laws to prevent occupational hazards Screening methods for Papillary Thyroid carcinoma Saving money and using it in future research

Need for further studies Biological and microcellular level research Exact mechanism of association

Concluding remarks

1. Fairweather D, Frisancho-Kiss S, Rose NR. Sex differences in autoimmune disease from a pathological perspective. The American journal of pathology. 2008;173(3):600-609.2. Chistiakov DA. Immunogenetics of hashimoto's thyroiditis. J Autoimmune Dis. 2005;2(1):1. doi: 1740-2557-2-1 [pii].3. American Autoimmune Related Diseases Association. Inc.Autoimmune Statistics. 2011.4. Ringold DA, Nicoloff JT, Kesler M, Davis H, Hamilton A, Mack T. Further evidence for a strong genetic influence on the development of autoimmune thyroid disease: The california twin study. Thyroid. 2002;12(8):647-653.5. Saranac L, Zivanovic S, Bjelakovic B, Stamenkovic H, Novak M, Kamenov B. Why is the thyroid so prone to autoimmune disease? Horm Res Paediatr. 2011;75(3):157-165. doi: 10.1159/000324442 [doi].6. Fukata S, Kuma K, Sugawara M. Relationship between cigarette smoking and hypothyroidism in patients with hashimoto's thyroiditis. J Endocrinol Invest. 1996;19(9):607-612. 7. Vargas M, Briones-Urbina R, Gladman D, Papsin F, Walfish P. Antithyroid microsomal autoantibodies and HLA-DR5 are associated with postpartum thyroid dysfunction: Evidence supporting an autoimmune pathogenesis*. The Journal of Clinical Endocrinology & Metabolism. 1988;67(2):327-333.

References

8. Magrini A, Pietroiusti A, Coppeta L, et al. Shift work and autoimmune thyroid disorders. Int J Immunopathol Pharmacol. 2006;19(4 Suppl):31-36. doi: 7 [pii].9. Repplinger D, Bargren A, Zhang Y, Adler JT, Haymart M, Chen H. Is hashimoto's thyroiditis a risk factor for papillary thyroid cancer? J Surg Res. 2008;150(1):49-52.10. Viswanathan AN, Hankinson SE, Schernhammer ES. Night shift work and the risk of endometrial cancer. Cancer Res. 2007;67(21):10618-10622. doi: 67/21/10618 [pii].11. Schernhammer ES, Feskanich D, Liang G, Han J. Rotating night-shift work and lung cancer risk among female nurses in the united states. Am J Epidemiol. 2013;178(9):1434-1441. doi: 10.1093/aje/kwt155 [doi].12. Bhatti P, Cushing-Haugen KL, Wicklund KG, Doherty JA, Rossing MA. Nightshift work and risk of ovarian cancer. Occup Environ Med. 2013;70(4):231-237. doi: 10.1136/oemed-2012-101146 [doi].13. Hedström AK, Åkerstedt T, Hillert J, Olsson T, Alfredsson L. Shift work at young age is associated with increased risk for multiple sclerosis. Ann Neurol. 2011;70(5):733-741.14. Burdelak W, Peplonska B. Night work and health of nurses and midviwes--a review. Med Pr. 2013;64(3):397-418.

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