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 Former President - IMA Tiruvallur Branch # 5, Jayanagar, Tiruvallur - 602 001 + 91 93805 21221, (044) 3760 9226 Dr. Sarma@works 2

The Purpose 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 Dr. Sarma@works puzzles of interaction of fluoride & 4

cause - effect Dr. Sarma@works 5

F and I in Fight FLOURIDE IODINE Thyroid is the battle ground Dr. Sarma@works 6

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 7

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 8

Hormone regulation Dr. Sarma@works 9

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 10

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 11

The Iodine Cycle Dr. Sarma@works 12

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 13

T 4 Catabolism Dr. Sarma@works 14

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 15

UNICEF Map of Fluorosis Dr. Sarma@works 16

Fluorosis in India According to UNICEF 15 States in India are endemic for fluorosis Dr. Sarma@works 17

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 and deep waters in nine states in India. • This is beyond the permissible limit Dr. Sarma@works 18

Research studies Dr. Sarma@works 19

studies from Dr. Sarma@works our country 20

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 May 27, 1972 - T. K. DAY & P. R. POWELL-JACKSON, PThe<Lancet, 0. 01 Fluoride, Water hardness and Endemic goitre Dr. Sarma@works • Goitre prevalence v/s hardness - P > 21

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 22

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 • In abundance of Iodine this does not occur • If total Iodine pool is low – It imposes a serious limitation on hormone synthesis 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. • 5 to 10 mg of fluoride daily for long periods Dr. Sarma@works 23 reduced hyperthyroidism in animal

4. Punjab endemic areas • In the neighborhood of Hundewali, Aravalli rocks emerge through the alluvium. • 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 high fluoride content The Lancet, Februarywith 15, 1981; Fluorine in the etiology of endemicof goitre by DAGMAR CURJEL WILSON, M. D. WOMEN'S MEDICAL SERVICE, INDIA (RETD. ) water and also dental fluorosis – the milder Dr. Sarma@works form of Fluorosis 24

5. The Assam Story 1. It is colourless, odourless water that is wreaking havoc on hundreds of thousands of people in many families in Assam. 2. Around 2, 000 people are in the grip of hydrofluorosis. 3. In Karbi Anglong, Naogaon and Kamrup districts, hundreds of villages are endemic due to excess fluoride. 4. More than six million children suffer from fluorosis. Of these, at least 25, 000 are in Assam. Health News, India : Fluoride in water takes its toll in Assam A SPECIAL FEATURE ARTICLE ON 23 -June-2004 5. In Karbi Anglong, one-seventh of its 7, 000 Dr. Sarma@works 25 people suffer from either dental or skeletal

5. The Assam Story contd. . 6. Fluoride levels were found to be as high as 5 to 23 mg per liter, The permissible limit according to WHO is only 1. 5 mg/L 7. Unfortunately, fluorosis has no cure. The only way out is prevention at an early stage. 8. Initial symptoms are sporadic pain and stiffness of joints, going into chronic joint pain, arthritis and calcification of ligaments. Symptoms of hypothyroidism develop slowly 9. Fluoride can enter the human body through food, Health News, India : Fluoride in water takes its toll in Assam A SPECIAL FEATURE ARTICLE toothpaste, mouth rinses and, ON of 23 -June-2004 course, more swiftly Dr. Sarma@works 26 through drinking water.

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. Chinoy et al. “Thyroid, Flurosis and prostatic monosaccharides" • Thyroid hormones regulate prostatic Int J Androl 23(3): 156 -62 (2000 Dr. Sarma@works glycoprotein metabolism – and Sialic acid 27

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 children Dr. Sarma RVSN et al – ICMR specialprevalent report to ITDA in AP 1983 6% Dr. Sarma@works • No skeletal fluorosis was detected in this study 28

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 29 effects was done

8. Fluorosis in Krishnagiri contd. . 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 30

study from Europe Dr. Sarma@works 31

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. CURJEL positively Absence of. INDIA dental DAGMAR WILSON, correlated; M. D. WOMEN'S MEDICAL SERVICE, (RETD. ) Dr. Sarma@works fluorosis in the control area where endemic 32

studies from china Dr. Sarma@works 33

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/T 3 was 7. 91 r. T 3 58 ng/dl, • 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 34 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 35

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. 19879%. The study of sub clinical endemic cretinism in Fujian province. cretinism Proceedings of the 3 rd National Conference on Endemic Goitre and Endemic Cretinism. Centre for Endemic Disease cretinism Control and Research, pp 120 -125. Dr. Sarma@works • Chinese Sub-clinical endemic in children 36 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 mg/l, Yang Y, Wang Low [Effects of high iodine and 2. 08 high fluorine, X, Guo X. Dr. Sarma@works I 131 uptake 3 and 9. 36 and 9. 26 High 37

studies from Russia Dr. Sarma@works 38

14. Water Fluoride and Thyroid Parameter examined Clinical Diagnosis Group A Healthy Group B Group C Hyperthyroid Hypothyro id Number of subjects 47 43 ↑ fluorine content (122 +/- 5 mμmol/l of water T 3↓ TSH↑, Mild Worsened improvement RAIU↑ No change normal F of 52 +/- 5 mμmol/l in water 33 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 39

15. Fluorosis - Immunity • In factory workers continuously exposed to fluorine • Thyroid and immune statuses were studied • The workers with euthyroid status – immune disorders with an allergic tendency – increase of B-lymphocytes, immunoglobulin A • Sub-clinical hypothyrodism cases – the immune alterations were more evident, – T-lymphocytes count↑, but their functional Dr. Sarma@works activity declined, indicating impaired T Ter Arkh. 1995; 67(1): 41 -2. The thyroid and immune statuses of workers with long-term fluorine exposure : Balabolkin MI, Mikhailets ND, Lobovskaia RN, Chernousova NV. 40

16. 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 – Moderate reduction of iodine-absorbing function of 41

17. Fluorosis- Calcitonin • Workers engaged in fluorine production were studied • RIA of thyrotropin and thyroid hormones in the blood • Moderate functional impairment of the hypophysis-thyroid gland system without overt hypo thyroidism • Elevation of calcitonin concentration indicated stimulation of thyroid gland’s Gig Tr Prof Zabol. 1989(9): 19 -22. Chronic effects of fluorides on the pituitary-thyroid system in industrial workers, parafollicular cells. Tokar' VI, Voroshnin VV, Sherbakov SV. Dr. Sarma@works 42

Pathogenesis Dr. Sarma@works 43

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 44

Depletion of Colloid Dr. Sarma@works 45

Empty Acinar Appearance Dr. Sarma@works 46

Pseudopodia Engulf Colloid Dr. Sarma@works ELECTRON MICROGRAPH 47

biochemical basis Dr. Sarma@works 48

Fluoride may Affect 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 49

Biochemical Basis 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. 50

Clinical aspects Dr. Sarma@works 51

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 52

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 • Person Abnormal with skeletal Dr. Sarma@works fluorosis can not. 53

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 54

Diagnostic Tests • FT 4, TSH to diagnose clinical & sub-clinical hypo function • FT 3 to identify low T 3 syndrome, r. T 3 and T 3/r. 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 Hypofunction 55

Clinical Photographs Dr. Sarma@works 56

Higher Grades of Goitre Dr. Sarma@works 57

Grade IV Goitre Mother with Grade IV Goitre Dr. Sarma@works Her son with MR 58

Grade IV Goitre Multinodular Gr IV Goitre Dr. Sarma@works Goitre in Himalayan belt 59

Skeletal Fluorosis Dr. Sarma@works 60

Skeletal Fluorosis Dr. Sarma@works 61

Skeletal Fluorosis Dr. Sarma@works 62

Skeletal Fluorosis Dr. Sarma@works 63

Skeletal Fluorosis Dr. Sarma@works 64

Dental Fluorosis Dr. Sarma@works 65

Dental Fluorosis Dr. Sarma@works 66

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 67

Future Research Needs 1. Methodologically rigorous studies on the cause effect relationship of Fluorosis and Thyroid function 2. Multidisciplinary approach for such studies 3. The exact mechanism of thyroid functional derangement needs to be elucidated 4. Combined clinico-epidemiological studies on endemic fluorosis in areas of endemic goitre 5. Study on drugs which can modify fluoride Dr. Sarma@works toxicity 68

Our Obeisance ‘Sukham Samagram Vijnane Vimale cha Pratishthitam’ - Charaka Samhita All happiness is rooted Science in the Good - Charaka Samhita Dr. Sarma@works 69

Thank You One and All Dr. Sarma@works 70