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1 2 Fluorosis AND THYROID Dr.R.V.S.N.Sarma, M.D., M.Sc., (Canada) Consultant Physician & Chest Specialist President - IMA Tiruvallur Branch.

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Presentation on theme: "1 2 Fluorosis AND THYROID Dr.R.V.S.N.Sarma, M.D., M.Sc., (Canada) Consultant Physician & Chest Specialist President - IMA Tiruvallur Branch."— Presentation transcript:

1 1

2 2 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 , (044)

3 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.

4 4 FLOURIDE Thyroid is the battle ground F and I in Fight IODINE

5 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 I 2 availability to thyroid and causes hypofunction In our country both deficiency of I 2 and excess of F 2 are endemic (endemic goitre and endemic fluorosis).

6 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


8 8 There are following 5 steps in the hormonogenesis 1.Trapping inorganic Iodine from dietary Iodides 2.Activation of Iodine to high valance I 2 3.Incorporation of I 2 into Tyrosine of Thyroid Globulin 4.Coupling of formed MIT and DIT to form T 4 & T 3 5.Proteolysis of Thyroglobulin to release T 4 & T 3 Hormonogenesis

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

10 10 UNICEF Map of Fluorosis

11 11 Fluorosis in India 15 states

12 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

13 13 studies from our country

14 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, T. K. DAY & P. R. POWELL-JACKSON, Fluoride, Water hardness and Endemic goitre

15 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:

16 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: Effect of fluorine on thyroid metabolism in hyperthyroidism - PIERRE-M. GALLETTI, M.D., PH.D* AND GUSTAVE JOYET, D.Sc.

17 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.)

18 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

19 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

20 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): (2000

21 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

22 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 , Report 121 – Mapping and fluoride dependence on water quality in Krishnagiri, Tamilnadu: G Karthikeyan, A Shunmugasundarraj.

23 23 study from Europe

24 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.)

25 25 studies from china

26 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 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.

27 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.

28 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 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

29 29 Parameter examinedLow I, High F areaControl area Thyromegaly Adults3.8%< 1 % Thyromegaly Children29.8%< 5 % Dental fluorosis Adults35.48%Absent Dental fluorosis Child72.9%,Low Average I.Q of pupil / /- 6.2 Urinary IodineLow mcg/l Urinary Fluorine2.08 mg/l,Low I 131 uptake 3 and 24 h9.36 and 9.26High Serum TSH levelsHigherNormal 13. Shandong Study Zhonghua Liu Xing Bing Xue Za Zhi Oct;15(5): [Effects of high iodine and high fluorine, Yang Y, Wang X, Guo X.

30 30 studies from Russia

31 31 Parameter examinedGroup AGroup BGroup C Clinical DiagnosisHealthyHyperthyroidHypothyroid Number of subjects fluorine content (122 +/- 5 mμmol/l of water T3 TSH, RAIU Mild improvement Worsened normal F of 52 +/- 5 mμmol/l in water No change 14. Water Fluoride and Thyroid Probl Endokrinol (Mosk) Nov-Dec;31(6):25-9. Body fluorine of healthy persons and thyroidopathy patients :Bachinskii PP, Gutsalenko OA, Naryzhniuk ND, Sidora VD, Shliakhta.

32 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.

33 33 Pathology Effect of sodium fluoride on the thyroid glands 1.Depletion of colloid from the follicles. 2.Shrinkage of follicles. 3.Disruption of follicular basement membrane 4.Edema and degeneration of the follicular epithelial cells. 5.Increased follicular vascularity. 6.Fatty degeneration in the inter-follicular connective tissue. 7.Vacuolations in the colloid

34 34 Empty Acinar Appearance

35 35 Pseudopodia Engulf Colloid ELECTRON MICROGRAPH

36 36 biochemical basis

37 37 1.Iodine pump, Peroxidase reactions 2.Coupling reactions, Lysosomal hydrolysis 3.Peripheral conversion of T4 to T3, Reverse T3 4.Hypothalamic TRH causes TSH release from thyrotroph using DAG/IP3/Ca 2+ mechanism (Gq) 5.TSH via cAMP (Gs/PKA) mechanism activates all aspects of follicular cell thyroid hormone synthesis, processing and release, as well as cell growth Hormonogenesis Affected

38 38 Adenyl Cyclase (AC) 1.TSH stimulation of thyroid Adenyl Cyclase (AC) is absolutely dependent on the regulatory nucleotides, the G proteins 2.Sodium fluoride has dual actions on AC 3.The AC activity increased as the concentration of NaF increased from 0.01 to 1 mM, 4.PFDA alters biochemical processes at cellular level 5.Fluoride stimulation of Adenyl Cyclase (AC) activity is two to three fold higher than that of TSH.

39 39 Clinical aspects

40 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.

41 41 UNICEFs 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

42 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

43 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

44 44 Clinical Photographs

45 45 Higher Grades of Goitre

46 46 Mother with Grade IV GoitreHer son with MR Grade IV Goitre

47 47 Multinodular Gr IV Goitre Goitre in Himalayan belt Grade IV Goitre

48 48 Skeletal Fluorosis

49 49 Skeletal Fluorosis

50 50 Skeletal Fluorosis

51 51 Skeletal Fluorosis

52 52 Skeletal Fluorosis

53 53 Dental Fluorosis

54 54 Dental Fluorosis

55 55 Summary 1.Fluorosis negatively affects Thyroid function 2.This association is seen in many studies from our country as well as others 3.Effects may range from simple goitre, sub clinical hypothyroidism to frank hypothyroidism 4.FT3, rT3 and rT3/T3 ratio need to be estimated in addition to FT4 and TSH 5.Sialic acid levels will be decreased in fluorosis 6. Adenyl Cyclase (AC) through G reg. protein - mechanism 7.In our country we need to be vigilant – both are endemic

56 56 Resources Consulted Second Look – NLM – NCBI – Pub Med searches FAN – Fluoride Action Network – ISFFR – International Society for Fluorosis Research FLUORIDE – Official Journal of ISFFR PFPC website – on Thyroid UNICEF publications Endocrine Regulations – China Endemic medical problems of India – a book

57 57 Our Obeisance Sukham Samagram Vijnane Vimale cha Pratishthitam All happiness is rooted in the Good Science - Charaka Samhita

58 58 Thank You One and All

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