3 ObjectivesTo present a ‘Snapshot’ view of the available evidence on the interaction of Fluorosis and Thyroid functionTo sensitize the clinicians on the possible role of fluoride as a putative cause in hypothyroidism and to present some clinical guidelinesTo 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 Thyroid is the battle ground F and I in FightFLOURIDEIODINEThyroid is the battle ground
5 The Two Halogen StoryFluorine and Iodine – both belong to the Halogen groupFluorine is more reactive than Chlorine > Bromine > IodineBoth occur as soluble salts in water and are ingestedFluorine is competitive to Iodine in chemical reactionsIodine ↓causes Goitre, Fluoride excess competitively inhibits I2 availability to thyroid and causes hypofunctionIn our country both deficiency of I2 and excess of F2 are endemic (endemic goitre and endemic fluorosis).
6 Cause – Effect Relationship Exposure to F must be for a prolonged period of timeThe damage is proportional to the administered doseFluoride dose has to be of toxic level – dose responseAnatomic & functional changes of the thyroid take time.Variable period of latency before changes manifestAn altered thyroid-hypophysial balance is the earliestLater parenchymal hypertrophy of thyroid gland occursLeads to a hypofunction of the thyroid, andFinally the ‘strumiform’ degeneration of gland sets in
7 Thyroid Regulation HYPOTHALAMUS - TRH ANT. PITUITARY - TSH TSH -R THYROID T4 and T3PLASMA T4 to FT4PLASMA T3 to FT3TISSUES T4 to T3, rT3
8 Hormonogenesis There are following 5 steps in the hormonogenesis Trapping inorganic Iodine from dietary IodidesActivation of Iodine to high valance I2Incorporation of I2 into Tyrosine of Thyroid GlobulinCoupling of formed MIT and DIT to form T4 & T3Proteolysis of Thyroglobulin to release T4 & T3
9 What happens in Fluorosis ? Normal catabolism -ThyroxineFT T3rT3 will be LOWrT3 ÷ T3 ratio will be LOWNormal deiodination of T4Abnormal catabolism -ThyroxineFT T3rT3 will be HIGHrT3 ÷ T3 ratio will be HIGHFluoride affects the normaldeiodination of T4rT3rT3
12 Fluoride in Our WatersDrinking 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
14 1. Himalayan Belt 17 villages of endemic goitre in Himalayan belt Water samples were analyzed for iodine content, fluoride level and hardnessGoitre prevalence v/s iodine content - P < 0.01Goitre prevalence v/s fluoride content - P < 0.01Goitre prevalence v/s hardness - P > 0.06The Lancet, May 27, T. K. DAY & P. R. POWELL-JACKSON, Fluoride, Water hardness and Endemic goitre
15 2. Dental Fluorosis and Goitre 22,276 individuals were examined in GujaratPresence of goitre and dental fluorosisFluoride and iodine content of the water testedGoitre prevalence 14.1%, Fluorosis 12.2%Only 0.3 % were Goitre of Grade II or moreAll cases of goitre were euthyroidOnly anatomical but no functional effectDesai VK, et al. (1993). Epidemiological study of goitre in endemic fluorosis district of Gujarat. Fluoride. 26:
16 3. Fluoride in Hyperthyroidism NaF 5 mg t.i.d was given to 19 pt of hyperthyroidThyroidal, blood and urinary radio-iodine studiesFluoride inhibits thyroid iodide concen. mechanismIf total Iodine pool is low – It imposes a serious limitation on hormone synthesis5 to 10mg of fluoride daily for long periods reduced hyperthyroidismJournal 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 4. Punjab endemic areasIn the neighborhood of Hundewali, Aravalli rocksSamples 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 5. The Assam StoryAround 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 hypofunctionHealth News, India : Fluoride in water takes its toll in Assam A SPECIAL FEATURE ARTICLE ON 23-June-2004
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 slowlyFluoride 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 6. Sialic Acid - Fluorosis Effect of fluoride in 36 villages of Mehsana district, North Gujarat was studiedConcentration of Sialic acid was significantly decreased (P < 0.01) in the fluorotic population as compared to control populationSialic acid concentration is now a marker for the diagnosis of fluorosis.Thyroid hormones regulate prostatic glycoprotein metabolism – and Sialic acid levelsChinoy et al. “Thyroid,Flurosis and prostatic monosaccharides" Int J Androl 23(3): (2000
21 7. Tribal Areas of Vizag -AP Upon invitation by the ITDA of Andhra PradeshWe have lead an ICMR team of doctors to study Goitre in Paderu taluk of Vizag district in A.P. in the year 1983Myself, 2 Asst. professors from Medicine and PSM - AMCThe tribals of Paderu, Munchenput, Seethampet have high prevalence(26%) of endemic goitre of iodine deficiencyDental fluorosis was seen prevalent in children 6%No skeletal fluorosis was detected in this studyThis study did not include blood tests for thyroid functionDr.Sarma RVSN et al – ICMR special report to ITDA AP 1983
22 8. Fluorosis in Tamilnadu Drinking water samples from 255 villages in the Krishnagiri block of Dharmapuri district of Tamilnadu were analyzedFluoride endemic areas of the region were identifiedThe prevalence of dental fluorosis is found – the high and lowThe relationship of fluoride on drinking water was assessed by simple and multiple correlation analysis.Clinical survey for Dental, Skeletal & thyroid effects was doneDental Fluorosis, Skeletal Fluorosis, Thyroid hypofunctionFluoride Vol. 33 No , Report 121 – Mapping and fluoride dependence on water quality in Krishnagiri, Tamilnadu: G Karthikeyan, A Shunmugasundarraj.
24 9. The Somerset StudyIn Somerset, England, in the rural district of Longport, in the rural areas of Charlton Mandeville and Long Sutton378 children in seven local schools were examined.An adjoining village of Somerton, was the control, and all the 203 children in four schools were examinedHigh Incidence of dental fluorosis and Goitre were positively correlated; Absence of dental fluorosis in the control area where endemic goitre was absentThe Lancet, February 15, 1981; Fluorine in the etiology of endemic goitre by DAGMAR CURJEL WILSON, M.D. WOMEN'S MEDICAL SERVICE, INDIA (RETD.)
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 TSH ↑, FT4 and FT3 NormalArea A – low Iodine, high fluoride – rT3 58 ng/dl, rT3/T3 was 7.91Area B – low Iodine, normal fluoride - rT3 32 ng/dl, rT3/T3 was 5.80Area C – Iodine supl. normal fluoride - rT3 21 ng/dl, rT3/T3 was 2.90The 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 11. Xingjian Experience769 school children 7 to 14 yrs. in three areas studied104 children with MR were detected in all.Area A – low Iodine, High fluoride – 25% MRArea B – low Iodine, normal fluoride – 16% MRArea C – Iodine supplemented and Normal fluoride – 8%A low iodine intake + high fluoride intake ↑ the somatic and the CNS developmental disturbance of iodine deficiencyIodine 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 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 significantTotal 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 13. Shandong Study Thyromegaly Adults 3.8% < 1 % Parameter examinedLow I, High F areaControl areaThyromegaly Adults3.8%< 1 %Thyromegaly Children29.8%< 5 %Dental fluorosis Adults35.48%AbsentDental fluorosis Child72.9%,LowAverage I.Q of pupil/- 7.75/- 6.2Urinary Iodinemcg/lUrinary Fluorine2.08 mg/l,I 131 uptake 3 and 24 h9.36 and 9.26HighSerum TSH levelsHigherNormalZhonghua Liu Xing Bing Xue Za Zhi Oct;15(5): [Effects of high iodine and high fluorine, Yang Y, Wang X, Guo X.
31 14. Water Fluoride and Thyroid Parameter examinedGroup AGroup BGroup CClinical DiagnosisHealthyHyperthyroidHypothyroidNumber of subjects474333↑ fluorine content (122 +/- 5 mμmol/l of waterT3↓ TSH↑,RAIU↑Mild improvementWorsenednormal F of 52 +/- 5 mμmol/l in waterNo changeProbl 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 15. Industrial FluorosisIn 165 workers of electrolysis shops of aluminum productionWith expressed signs of chronic fluoride intoxicationCorrelated with longer service and fluorosis progressToxic 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 wereLow T3 with normal T4 level, and an↑in TSH.Probl Endokrinol 1996; 42: Thyroid function during prolonged exposure to fluorides. MIKHAILETS ND, BALABOLKIN MI, RAKITIN VA, DANILOV IP.
33 Pathology Effect of sodium fluoride on the thyroid glands Depletion of colloid from the follicles.Shrinkage of follicles.Disruption of follicular basement membraneEdema and degeneration of the follicular epithelial cells.Increased follicular vascularity.Fatty degeneration in the inter-follicular connective tissue.Vacuolations in the colloid
37 Hormonogenesis Affected Iodine pump, Peroxidase reactionsCoupling reactions, Lysosomal hydrolysisPeripheral 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
38 Adenyl Cyclase (AC)TSH stimulation of thyroid Adenyl Cyclase (AC) is absolutely dependent on the regulatory nucleotides, the G proteinsSodium fluoride has dual actions on ACThe AC activity increased as the concentration of NaF increased from 0.01 to 1 mM,PFDA alters biochemical processes at cellular levelFluoride stimulation of Adenyl Cyclase (AC) activity is two to three fold higher than that of TSH.
40 Fluorosis Fluoride Toxicity Nausea, vomiting, diarrhea, abdominal pain,numbness/tingling in extremitiesFluorosisPitted enamel and discoloration of the teethSkeletal Fluorosis – pain and stiffness of joints, going into chronic joint pain, arthritis and calcification of ligaments etc.
41 UNICEF’s Clinical Test Three simple clinical testsForward flexion of spineChin to Chest testHands on the occiput testNormal person can doPerson with skeletal fluorosis can not.Left figures Normal, Right Abnormal
42 For The Clinicians Look for signs of Fluoride excess May be clinically euthyroidHypothyroidism itself is a subtle diseaseHigh index of suspicion is neededAssociation with fluorosis must be thoughtEspecially if the pt is from fluorosis endemic regionGoitre, clinical and sub-clinical cretinism in childrenA word of caution on use of NaF for otosclerosis
43 Diagnostic TestsDon’t do Total T4, T3 – Only FT4 and TSH are to be doneFT3 to identify low T3 syndrome, rT3 and rT3/T3 ratioSialic Acid in plasma and urine, urinary fluoride excretionDrinking water sample analysis for fluoride levelsChronology of Thyroid Function Test abnormalities1. Normal FT4, FT3, ↑TSH – Sub clinical Hypofunction2. Normal FT4, FT3, ↑TSH, ↑rT3 – Sub clinical Hypofunction3. Normal FT4, FT3, ↑TSH, ↑rT3 , ↑rT3 /T3 ratio - Sub clinical4. Normal FT4, ↓FT3, ↑TSH, ↑rT3 , ↑rT3 /T3 ratio –↓T3 syn5. FT4↓,↓FT3, ↑TSH, ↑rT3 , ↑rT3 /T3 ratio – Frank Hypo
55 Summary Fluorosis negatively affects Thyroid function This association is seen in many studies from our country as well as othersEffects may range from simple goitre, sub clinical hypothyroidism to frank hypothyroidismFT3, rT3 and rT3/T3 ratio need to be estimated in addition to FT4 and TSHSialic acid levels will be decreased in fluorosis↑ Adenyl Cyclase (AC) through G reg. protein - mechanismIn our country we need to be vigilant – both are endemic
56 Resources Consulted Second Look – www.SLweb.org NLM – NCBI – Pub Med searchesFAN – Fluoride Action Network –ISFFR – International Society for Fluorosis ResearchFLUORIDE – Official Journal of ISFFRPFPC website – on ThyroidUNICEF publicationsEndocrine Regulations – ChinaEndemic medical problems of India – a book
57 Sukham Samagram Vijnane Vimale cha Pratishthitam Our ObeisanceSukham Samagram Vijnane Vimale cha PratishthitamAll happiness is rooted in the Good Science- Charaka Samhita