Dr.Sarma@works

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

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

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

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

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

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

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

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 rT3 rT3 Dr.Sarma@works

UNICEF Map of Fluorosis Dr.Sarma@works

Fluorosis in India 15 states Dr.Sarma@works

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

studies from our country Dr.Sarma@works

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

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

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

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

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

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

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

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

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

study from Europe Dr.Sarma@works

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

studies from china Dr.Sarma@works

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

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

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

13. Shandong Study Thyromegaly Adults 3.8% < 1 % Parameter examined Low I, High F area Control area Thyromegaly Adults 3.8% < 1 % Thyromegaly Children 29.8% < 5 % Dental fluorosis Adults 35.48% Absent Dental fluorosis Child 72.9%, Low Average I.Q of pupil 76.67 +/- 7.75 88.88 +/- 6.2 Urinary Iodine 816.25 mcg/l Urinary Fluorine 2.08 mg/l, I 131 uptake 3 and 24 h 9.36 and 9.26 High Serum TSH levels Higher Normal 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

studies from Russia Dr.Sarma@works

14. Water Fluoride and Thyroid Parameter examined Group A Group B Group C Clinical Diagnosis Healthy Hyperthyroid Hypothyroid Number of subjects 47 43 33 ↑ 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 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

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

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

Empty Acinar Appearance Dr.Sarma@works

Pseudopodia Engulf Colloid Dr.Sarma@works ELECTRON MICROGRAPH

biochemical basis Dr.Sarma@works

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

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

Clinical aspects Dr.Sarma@works

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

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

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

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

Clinical Photographs Dr.Sarma@works

Higher Grades of Goitre Dr.Sarma@works

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

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

Skeletal Fluorosis Dr.Sarma@works

Skeletal Fluorosis Dr.Sarma@works

Skeletal Fluorosis Dr.Sarma@works

Skeletal Fluorosis Dr.Sarma@works

Skeletal Fluorosis Dr.Sarma@works

Dental Fluorosis Dr.Sarma@works

Dental Fluorosis Dr.Sarma@works

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

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 Endocrine Regulations – China Endemic medical problems of India – a book Dr.Sarma@works

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

Thank You One and All Dr.Sarma@works