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Fluorosis AND THYROID

Fluorosis AND THYROID. Dr.R.V.S.N.Sarma, M.D., M.Sc., (Canada) Consultant Physician & Chest Specialist President - IMA Tiruvallur Branch # 5, Jayanagar, Tiruvallur - 602 001 + 91 93805 21221, (044) 2766 0593. Objectives.

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Fluorosis AND THYROID

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  1. Dr.Sarma@works

  2. FluorosisAND THYROID Dr.R.V.S.N.Sarma, M.D., M.Sc., (Canada) Consultant Physician & Chest Specialist President - IMA Tiruvallur Branch # 5, Jayanagar, Tiruvallur - 602 001 + 91 93805 21221, (044) 2766 0593 Dr.Sarma@works

  3. Objectives • To present a ‘Snapshot’ view of the available evidence on the interaction of Fluorosis and Thyroid function • To sensitize the clinicians on the possible role of fluoride as a putative cause in hypothyroidism and to present some clinical guidelines • To request the elite group of researchers working on fluorosis – to take up well designed studies to answer some of the puzzles of interaction of fluoride & thyroid. Dr.Sarma@works

  4. F and I in Fight FLOURIDE IODINE Thyroid is the battle ground Dr.Sarma@works

  5. The Two Halogen Story • Fluorine and Iodine – both belong to the Halogen group • Fluorine is more reactive than Chlorine > Bromine > Iodine • Both occur as soluble salts in water and are ingested • Fluorine is competitive to Iodine in chemical reactions • Iodine ↓causes Goitre, Fluoride excess competitively inhibits I2 availability to thyroid and causes hypofunction • In our country both deficiency of I2 and excess of F2 are endemic (endemic goitre and endemic fluorosis). Dr.Sarma@works

  6. Cause – Effect Relationship • Exposure to F must be for a prolonged period of time • The damage is proportional to the administered dose • Fluoride dose has to be of toxic level – dose response • Anatomic & functional changes of the thyroid take time. • Variable period of latency before changes manifest • An altered thyroid-hypophysial balance is the earliest • Later parenchymal hypertrophy of thyroid gland occurs • Leads to a hypofunction of the thyroid, and • Finally the ‘strumiform’ degeneration of gland sets in Dr.Sarma@works

  7. Thyroid Regulation HYPOTHALAMUS - TRH ANT. PITUITARY - TSH TSH -R THYROID T4 and T3 PLASMA T4 to FT4 PLASMA T3 to FT3 TISSUES T4 to T3, rT3 Dr.Sarma@works

  8. Hormonogenesis There are following 5 steps in the hormonogenesis • Trapping inorganic Iodine from dietary Iodides • Activation of Iodine to high valance I2 • Incorporation of I2 into Tyrosine of Thyroid Globulin • Coupling of formed MIT and DIT to form T4 & T3 • Proteolysis of Thyroglobulin to release T4 & T3 Dr.Sarma@works

  9. rT3 rT3 What happens in Fluorosis ? Normal catabolism -Thyroxine FT4 T3 rT3 will be LOW rT3 ÷ T3 ratio will be LOW Normal deiodination of T4 Abnormal catabolism -Thyroxine FT4 T3 rT3 will be HIGH rT3 ÷ T3 ratio will be HIGH Fluoride affects the normal deiodination of T4 Dr.Sarma@works

  10. UNICEF Map of Fluorosis Dr.Sarma@works

  11. Fluorosis in India 15 states Dr.Sarma@works

  12. Fluoride in Our Waters • Drinking water should not contain more than 1.5 ppm of fluoride (WHO, 1994). • A much elevated concentration of fluoride, ranging from more than 1.5 ppm to 20 ppm in surface, subsurface waters in nine states in India. • This is beyond the permissible limit Dr.Sarma@works

  13. studies from our country Dr.Sarma@works

  14. 1. Himalayan Belt • 17 villages of endemic goitre in Himalayan belt • Water samples were analyzed for iodine content, fluoride level and hardness • Goitre prevalence v/s iodine content - P < 0.01 • Goitre prevalence v/s fluoride content - P < 0.01 • Goitre prevalence v/s hardness - P > 0.06 The Lancet, May 27, 1972 - T. K. DAY & P. R. POWELL-JACKSON, Fluoride, Water hardness and Endemic goitre Dr.Sarma@works

  15. 2. Dental Fluorosis and Goitre • 22,276 individuals were examined in Gujarat • Presence of goitre and dental fluorosis • Fluoride and iodine content of the water tested • Goitre prevalence 14.1%, Fluorosis 12.2% • Only 0.3 % were Goitre of Grade II or more • All cases of goitre were euthyroid • Only anatomical but no functional effect Desai VK, et al. (1993). Epidemiological study of goitre in endemic fluorosis district of Gujarat. Fluoride. 26:187-90. Dr.Sarma@works

  16. 3. Fluoride in Hyperthyroidism • NaF 5 mg t.i.d was given to 19 pt of hyperthyroid • Thyroidal, blood and urinary radio-iodine studies • Fluoride inhibits thyroid iodide concen. mechanism • If total Iodine pool is low – It imposes a serious limitation on hormone synthesis • 5 to 10mg of fluoride daily for long periods reduced hyperthyroidism Journal of Clinical Endocrinology 1978; 18:1102-1110. Effect of fluorine on thyroid metabolism in hyperthyroidism - PIERRE-M. GALLETTI, M.D., PH.D* AND GUSTAVE JOYET, D.Sc. Dr.Sarma@works

  17. 4. Punjab endemic areas • In the neighborhood of Hundewali, Aravalli rocks • Samples of these rocks were found to have fluorine content, varying from 30 to 3200 parts per million. • These extend between the Chenab and Ravi rivers, • The distribution of Endemic Goitre correlated with high fluoride content of water and also dental fluorosis. The Lancet, February 15, 1981; Fluorine in the etiology of endemic goitre by DAGMAR CURJEL WILSON, M.D. WOMEN'S MEDICAL SERVICE, INDIA (RETD.) Dr.Sarma@works

  18. 5. The Assam Story • Around 2,00,000 people are in the grip of hydro-fluorosis. • In Karbi Anglong, Naogaon and Kamrup districts, hundreds of villages are endemic due to excess fluoride. • More than six million children suffer from fluorosis. • Of these, at least 25,000 are in Assam. • 14% of its 7,00,000 people suffer from either dental or skeletal fluorosis. Many have thyroid hypofunction Health News, India : Fluoride in water takes its toll in Assam A SPECIAL FEATURE ARTICLE ON 23-June-2004 Dr.Sarma@works

  19. 5. The Assam Story contd.. • Fluoride levels were found to be as high as 5 to 23 mg per liter, • Unfortunately, fluorosis has no cure. The only way out is prevention at an early stage. • Initial symptoms are sporadic pain and stiffness of joints, going into chronic joint pain, arthritis and calcification of ligaments. Symptoms of hypothyroidism develop slowly • Fluoride can enter the human body through food, toothpaste, mouth rinses and, of course, more swiftly through drinking water. Health News, India : Fluoride in water takes its toll in Assam A SPECIAL FEATURE ARTICLE ON 23-June-2004 Dr.Sarma@works

  20. 6. Sialic Acid - Fluorosis • Effect of fluoride in 36 villages of Mehsana district, North Gujarat  was studied • Concentration of Sialic acid was significantly decreased (P < 0.01) in the fluorotic population as compared to control population • Sialic acid concentration is now a marker for the diagnosis of fluorosis. • Thyroid hormones regulate prostatic glycoprotein metabolism – and Sialic acid levels Chinoy et al. “Thyroid,Flurosis and prostatic monosaccharides" Int J Androl 23(3):156-62 (2000 Dr.Sarma@works

  21. 7. Tribal Areas of Vizag -AP • Upon invitation by the ITDA of Andhra Pradesh • We have lead an ICMR team of doctors to study Goitre in Paderu taluk of Vizag district in A.P. in the year 1983 • Myself, 2 Asst. professors from Medicine and PSM - AMC • The tribals of Paderu, Munchenput, Seethampet have high prevalence(26%) of endemic goitre of iodine deficiency • Dental fluorosis was seen prevalent in children 6% • No skeletal fluorosis was detected in this study • This study did not include blood tests for thyroid function Dr.Sarma RVSN et al – ICMR special report to ITDA AP 1983 Dr.Sarma@works

  22. 8. Fluorosis in Tamilnadu • Drinking water samples from 255 villages in the Krishnagiri block of Dharmapuri district of Tamilnadu were analyzed • Fluoride endemic areas of the region were identified • The prevalence of dental fluorosis is found – the high and low • The relationship of fluoride on drinking water was assessed by simple and multiple correlation analysis. • Clinical survey for Dental, Skeletal & thyroid effects was done • Dental Fluorosis, Skeletal Fluorosis, Thyroid hypofunction Fluoride Vol. 33 No. 3 121-127 2000, Report 121 – Mapping and fluoride dependence on water quality in Krishnagiri, Tamilnadu: G Karthikeyan, A Shunmugasundarraj. Dr.Sarma@works

  23. study from Europe Dr.Sarma@works

  24. 9. The Somerset Study • In Somerset, England, in the rural district of Longport, in the rural areas of Charlton Mandeville and Long Sutton • 378 children in seven local schools were examined. • An adjoining village of Somerton, was the control, and all the 203 children in four schools were examined • High Incidence of dental fluorosis and Goitre were positively correlated; Absence of dental fluorosis in the control area where endemic goitre was absent The Lancet, February 15, 1981; Fluorine in the etiology of endemic goitre by DAGMAR CURJEL WILSON, M.D. WOMEN'S MEDICAL SERVICE, INDIA (RETD.) Dr.Sarma@works

  25. studies from china Dr.Sarma@works

  26. 10. Sub-clinical Endemic Cretinism • Cretinism in iodine-deficiency areas is well known, • The milder form is called "semi-cretinism," or “cretinoidism.“ • It was named as "sub-clinical endemic cretinism" in a symposium held in Xinzhou, China 1985. TSH ↑, FT4 and FT3 Normal • Area A – low Iodine, high fluoride –rT3 58 ng/dl, rT3/T3 was 7.91 • Area B – low Iodine, normal fluoride - rT3 32 ng/dl, rT3/T3 was 5.80 • Area C – Iodine supl. normal fluoride - rT3 21 ng/dl, rT3/T3 was 2.90 • The excess fluoride ion affects normal deiodination. Iodine Deficiency Disorder Newsletter 1991 August Vol. 7 No. 3, The Relationship of a Low-Iodine and High-Fluoride rT3, rT3/T3 ratio in Xinjiang - Lin Fa-Fu, Aihaiti, Zhao Hong-Xin, Lin Jin, Jiang Ji-Yong, Maimaiti, and Aiken. Dr.Sarma@works

  27. 11. Xingjian Experience • 769 school children 7 to 14 yrs. in three areas studied • 104 children with MR were detected in all. • Area A – low Iodine, High fluoride – 25% MR • Area B – low Iodine, normal fluoride – 16% MR • Area C – Iodine supplemented and Normal fluoride – 8% • A low iodine intake + high fluoride intake ↑ the somatic and the CNS developmental disturbance of iodine deficiency Iodine Deficiency Disorder Newsletter 1991 August Vol. 7 No. 3, The Relationship of a Low-Iodine and High-Fluoride Environment to Sub-clinical Cretinism in Xinjiang - Lin Fa-Fu, Aihaiti, Zhao Hong-Xin, Lin Jin, Jiang Ji-Yong, Maimaiti, and Aiken. Dr.Sarma@works

  28. 12. Endemic Cretinism • (a) average IQ: 71, 77, 96; • (b) average auditory threshold (in dB):24, 20, 16; • (c) bone age retardation (%): 28, 13, 4; • (d) thyroid I131 uptake (%): 60, 50, 24; and • (e) serum TSH (mU/ml): 21, 11, 6. • All these differences are statistically significant • Total attack rate of sub-clinical endemic cretinism 9%. • Sub-clinical endemic cretinism in children with mental retardation was 69%, Ma Xin-Yuan, et al . 1987 The study of sub clinical endemic cretinism in Fujian province . Proceedings of the 3rd National Conference on Endemic Goitre and Endemic Cretinism. Chinese Centre for Endemic Disease Control and Research, pp 120-125. Dr.Sarma@works

  29. 13. Shandong Study Zhonghua Liu Xing Bing Xue Za Zhi. 1994 Oct;15(5):296-8. [Effects of high iodine and high fluorine, Yang Y, Wang X, Guo X. Dr.Sarma@works

  30. studies from Russia Dr.Sarma@works

  31. 14. Water Fluoride and Thyroid Probl Endokrinol (Mosk). 1985 Nov-Dec;31(6):25-9. Body fluorine of healthy persons and thyroidopathy patients :Bachinskii PP, Gutsalenko OA, Naryzhniuk ND, Sidora VD, Shliakhta . Dr.Sarma@works

  32. 15. Industrial Fluorosis • In 165 workers of electrolysis shops of aluminum production • With expressed signs of chronic fluoride intoxication • Correlated with longer service and fluorosis progress • Toxic involvement of the liver in fluorosis patients, • Low T3 syndrome is observed more frequently (in 75.6%) • Liver abnormalities lead to ↓in peripheral conversion of T4 to T3, • The detected thyroid abnormalities were • Low T3 with normal T4 level, and an↑in TSH. Probl Endokrinol 1996; 42: 6-9. Thyroid function during prolonged exposure to fluorides. MIKHAILETS ND, BALABOLKIN MI, RAKITIN VA, DANILOV IP. Dr.Sarma@works

  33. Pathology Effect of sodium fluoride on the thyroid glands • Depletion of colloid from the follicles. • Shrinkage of follicles. • Disruption of follicular basement membrane • Edema and degeneration of the follicular epithelial cells. • Increased follicular vascularity. • Fatty degeneration in the inter-follicular connective tissue. • Vacuolations in the colloid Dr.Sarma@works

  34. Empty Acinar Appearance Dr.Sarma@works

  35. Pseudopodia Engulf Colloid Dr.Sarma@works ELECTRON MICROGRAPH

  36. biochemical basis Dr.Sarma@works

  37. Hormonogenesis Affected • Iodine pump, Peroxidase reactions • Coupling reactions, Lysosomal hydrolysis • Peripheral conversion of T4 to T3↓, Reverse T3↑ • Hypothalamic TRH causes TSH release from thyrotroph using DAG/IP3/Ca2+ mechanism (Gq) • TSH via cAMP (Gs/PKA) mechanism activates all aspects of follicular cell thyroid hormone synthesis, processing and release, as well as cell growth Dr.Sarma@works

  38. Adenyl Cyclase (AC) • TSH stimulation of thyroid Adenyl Cyclase (AC) is absolutely dependent on the regulatory nucleotides, the G proteins • Sodium fluoride has dual actions on AC • The AC activity increased as the concentration of NaF increased from 0.01 to 1 mM, • PFDA alters biochemical processes at cellular level • Fluoride stimulation of Adenyl Cyclase (AC) activity is two to three fold higher than that of TSH. Dr.Sarma@works

  39. Clinical aspects Dr.Sarma@works

  40. Fluorosis Fluoride Toxicity • Nausea, vomiting, diarrhea, abdominal pain, • numbness/tingling in extremities Fluorosis • Pitted enamel and discoloration of the teeth • Skeletal Fluorosis – pain and stiffness of joints, going into chronic joint pain, arthritis and calcification of ligaments etc. Dr.Sarma@works

  41. UNICEF’s Clinical Test • Three simple clinical tests • Forward flexion of spine • Chin to Chest test • Hands on the occiput test • Normal person can do • Person with skeletal fluorosis can not. Left figures Normal, Right Abnormal Dr.Sarma@works

  42. For The Clinicians • Look for signs of Fluoride excess • May be clinically euthyroid • Hypothyroidism itself is a subtle disease • High index of suspicion is needed • Association with fluorosis must be thought • Especially if the pt is from fluorosis endemic region • Goitre, clinical and sub-clinical cretinism in children • A word of caution on use of NaF for otosclerosis Dr.Sarma@works

  43. Diagnostic Tests • Don’t do Total T4, T3 – Only FT4 and TSH are to be done • FT3 to identify low T3 syndrome, rT3 and rT3/T3 ratio • Sialic Acid in plasma and urine, urinary fluoride excretion • Drinking water sample analysis for fluoride levels Chronology of Thyroid Function Test abnormalities 1. Normal FT4, FT3, ↑TSH – Sub clinical Hypofunction 2. Normal FT4, FT3, ↑TSH, ↑rT3 – Sub clinical Hypofunction 3. Normal FT4, FT3, ↑TSH, ↑rT3 , ↑rT3 /T3 ratio - Sub clinical 4. Normal FT4, ↓FT3, ↑TSH, ↑rT3 , ↑rT3 /T3 ratio –↓T3 syn 5. FT4↓,↓FT3, ↑TSH, ↑rT3 , ↑rT3 /T3 ratio – Frank Hypo Dr.Sarma@works

  44. Clinical Photographs Dr.Sarma@works

  45. Higher Grades of Goitre Dr.Sarma@works

  46. Grade IV Goitre Mother with Grade IV Goitre Her son with MR Dr.Sarma@works

  47. Grade IV Goitre Multinodular Gr IV Goitre Multinodular Gr IV Goitre Goitre in Himalayan belt Dr.Sarma@works

  48. Skeletal Fluorosis Dr.Sarma@works

  49. Skeletal Fluorosis Dr.Sarma@works

  50. Skeletal Fluorosis Dr.Sarma@works

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