Dr Sarmaworks 1 Fluorosis AND THYROID Dr R

Dr. Sarma@works 1

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 Dr. Sarma@works 2

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 Dr. Sarma@works puzzles of interaction of fluoride & 3

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

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 Dr. Sarma@works competitively inhibits I 2 availability to thyroid and 5

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 Dr. Sarma@works • An altered thyroid-hypophysial balance is the 6

Thyroid Regulation HYPOTHALAMUS TR HANT. PITUITARY TSH -R THYROID T 4 and T 3 PLASMA T 4 to FT 4 PLASMA T 3 to FT 3 TISSUES T 4 to T 3, r. T 3 Dr. Sarma@works 7

Hormonogenesis 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 Dr. Sarma@works T 4 & T 3 8

What happens in Fluorosis ? Normal catabolism Thyroxine FT 4 T 3 r. T 3 will be LOW r. T 3 ÷ T 3 ratio will be LOW Normal deiodination of T 4 Dr. Sarma@works Abnormal catabolism Thyroxine FT 4 T 3 r. T 3 will be HIGH r. T 3 ÷ T 3 ratio will be HIGH Fluoride affects the normal deiodination of T 4 9

UNICEF Map of Fluorosis Dr. Sarma@works 10

Fluorosis in India 15 states Dr. Sarma@works 11

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 12

studies from Dr. Sarma@works our country 13

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 - The Lancet, May 27, 1972 - T. K. DAY & P. R. POWELL-JACKSON, P < 0. 01 Fluoride, Water hardness and Endemic goitre Dr. Sarma@works • Goitre prevalence v/s hardness - P > 14

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 Desai VK, et al. (1993). Epidemiological study of goitre in more endemic fluorosis district of Gujarat. Fluoride. 26: 187 -90. Dr. Sarma@works • All cases of goitre were euthyroid 15

3. Fluoride in Hyperthyroidism • Na. F 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 10 mg of fluoride daily for long periods Journal of Clinical Endocrinology 1978; 18: 1102 -1110. Effect of fluorine on thyroid metabolismreduced hyperthyroidism in hyperthyroidism - PIERRE-M. GALLETTI, M. D. , PH. D* AND GUSTAVE JOYET, D. Sc. Dr. Sarma@works 16

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 The Lancet, February 15, 1981; Fluorine in the etiology of endemic goitre by DAGMAR CURJEL WILSON, M. D. WOMEN'S MEDICAL SERVICE, INDIA (RETD. ) water and also dental fluorosis. Dr. Sarma@works 17

5. The Assam Story • Around 2, 000 people are in the grip of hydrofluorosis. • 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, 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 18

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 Health News, India : Fluoride in water takes its toll in Assam A SPECIAL FEATURE ARTICLE ON 23 -June-2004 through drinking water. Dr. Sarma@works 19

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 Chinoy et al. “Thyroid, Flurosis and prostatic monosaccharides" Int J Androl 23(3): 156 -62 (2000 Dr. Sarma@works glycoprotein metabolism – and Sialic acid 20

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 Dr. Sarma RVSN et al – ICMR special report to ITDA AP 1983 6% Dr. Sarma@works • No skeletal fluorosis was detected in this study 21

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. Fluoride Vol. 33 No. 3 121 -127 2000, Report 121 – Mapping and fluoride dependence on water quality in Krishnagiri, Tamilnadu: G Karthikeyan, A Shunmugasundarraj. • Clinical survey for Dental, Skeletal & thyroid Dr. Sarma@works 22 effects was done

study from Europe Dr. Sarma@works 23

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 The Lancet, February 15, 1981; Fluorine in the etiology of endemic goitre by were positively correlated; Absence of dental DAGMAR CURJEL WILSON, M. D. WOMEN'S MEDICAL SERVICE, INDIA (RETD. ) Dr. Sarma@works fluorosis in the control area where endemic 24

studies from china Dr. Sarma@works 25

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 ↑, FT 4 and FT 3 Normal • Area A – low Iodine, high fluoride – r. T 3 58 ng/dl, r. T 3/T 3 was 7. 91 • Area B – low Iodine, normal fluoride - r. T 3 32 ng/dl, r. T 3/T 3 was 5. 80 Iodine Deficiency Disorder Newsletter 1991 August Vol. 7 No. 3, The Relationship of a Low. Iodine High-Fluoride r. T 3, r. T 3/T 3 ratio in Xinjiang - Lin Fa-Fu, Aihaiti, Zhao Hong-Xin, Lin • and Area C – Iodine supl. normal fluoride - r. T 3 21 ng/dl, Jin, Jiang Ji-Yong, Maimaiti, and Aiken. Dr. Sarma@works 26 r. T 3/T 3 was 2. 90

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 Iodine Deficiency Disorder Newsletter 1991 August Vol. 7 No. 3, The Relationship of a Lowsomatic and the CNS developmental disturbance 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. of iodine deficiency Dr. Sarma@works 27

12. Endemic Cretinism • (a) average IQ: 71, 77, 96; • (b) average auditory threshold (in d. B): 24, 20, 16; • (c) bone age retardation (%): 28, 13, 4; • (d) thyroid I 131 uptake (%): 60, 50, 24; and • (e) serum TSH (m. U/ml): 21, 11, 6. • All these differences are statistically significant • Total attack rate of sub-clinical endemic Ma Xin-Yuan, et al. 1987 The study of sub clinical endemic cretinism in Fujian province. cretinism 9%. Proceedings of the 3 rd National Conference on Endemic Goitre and Endemic Cretinism. Centre for Endemic Disease Control and Research, pp 120 -125. Dr. Sarma@works • Chinese Sub-clinical endemic cretinism in children 28 with mental retardation was 69%,

13. Shandong Study Parameter examined Low I, High F area Control area Thyromegaly Adults 3. 8% Thyromegaly 29. 8% Children < 1 % < 5 % Dental fluorosis 35. 48% Adults Dental fluorosis 72. 9%, Child Average I. Q of pupil 76. 67 +/- 7. 75 Absent Low 88. 88 +/- 6. 2 Urinary Iodine Low 816. 25 mcg/l Zhonghua Liu Xing Bing Xue Za Zhi. 1994 Oct; 15(5): 296 -8. Urinary Fluorine Low [Effects of high iodine and 2. 08 mg/l, high fluorine, Yang Y, Wang X, Guo X. Dr. Sarma@works I 131 uptake 3 and 9. 36 and 9. 26 High 29

studies from Russia Dr. Sarma@works 30

14. Water Fluoride and Thyroid Parameter examined Clinical Diagnosis Group A Healthy Group B Group C Hyperthyroid Hypothyro id Number of subjects 47 43 33 ↑ fluorine content (122 T 3↓ Mild Worsened +/- 5 mμmol/l of water TSH↑, improvement RAIU↑ normal F of 52 +/- 5 No change No mμmol/l in water change 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 31

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 T 3 syndrome is observed more frequently (in 75. 6%) • Liver abnormalities lead to ↓in peripheral conversion of T 4 to T 3, Endokrinol 1996; 42: 6 -9. Thyroid function during prolonged exposure to fluorides. • Probl. The detected thyroid abnormalities were MIKHAILETS ND, BALABOLKIN MI, RAKITIN VA, DANILOV IP. Dr. Sarma@works – Low T 3 with normal T 4 level, and an↑in TSH. 32

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. Dr. Sarma@works follicular connective tissue. 7. Vacuolations in the colloid 33

Empty Acinar Appearance Dr. Sarma@works 34

Pseudopodia Engulf Colloid Dr. Sarma@works ELECTRON MICROGRAPH 35

biochemical basis Dr. Sarma@works 36

Hormonogenesis Affected 1. Iodine pump, Peroxidase reactions 2. Coupling reactions, Lysosomal hydrolysis 3. Peripheral conversion of T 4 to T 3↓, Reverse T 3↑ 4. Hypothalamic TRH causes TSH release from thyrotroph using DAG/IP 3/Ca 2+ mechanism (Gq) 5. TSH via c. AMP (Gs/PKA) mechanism activates all aspects of follicular cell thyroid hormone synthesis, processing and release, as well as cell growth Dr. Sarma@works 37

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 Na. F increased from 0. 01 to 1 m. M, 4. PFDA alters biochemical processes at cellular level 5. Fluoride stimulation of Adenyl Cyclase (AC) activity is two to three fold higher Dr. Sarma@works than that of TSH. 38

Clinical aspects Dr. Sarma@works 39

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 40

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 Left figures Normal, Right Abnormal • Person with skeletal Dr. Sarma@works fluorosis can not. 41

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 Dr. Sarma@works • A word of caution on use of Na. F for otosclerosis 42

Diagnostic Tests • Don’t do Total T 4, T 3 – Only FT 4 and TSH are to be done • FT 3 to identify low T 3 syndrome, r. T 3 and r. T 3/T 3 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 FT 4, FT 3, ↑TSH – Sub clinical Hypofunction 2. Normal FT 4, FT 3, ↑TSH, ↑r. T 3 – Sub clinical Dr. Sarma@works 43 Hypofunction

Clinical Photographs Dr. Sarma@works 44

Higher Grades of Goitre Dr. Sarma@works 45

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

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

Skeletal Fluorosis Dr. Sarma@works 48

Skeletal Fluorosis Dr. Sarma@works 49

Skeletal Fluorosis Dr. Sarma@works 50

Skeletal Fluorosis Dr. Sarma@works 51

Skeletal Fluorosis Dr. Sarma@works 52

Dental Fluorosis Dr. Sarma@works 53

Dental Fluorosis Dr. Sarma@works 54

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. FT 3, r. T 3 and r. T 3/T 3 ratio need to be estimated in addition to FT 4 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 Dr. Sarma@works endemic 55

Resources Consulted • Second Look – www. SLweb. org • NLM – NCBI – Pub Med searches • FAN – Fluoride Action Network – www. fan. org • ISFFR – International Society for Fluorosis Research • FLUORIDE – Official Journal of ISFFR • PFPC website – on Thyroid • UNICEF publications Dr. Sarma@works • Endocrine Regulations – China 56

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

Thank You One and All Dr. Sarma@works 58