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

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 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).

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

7. 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

8. 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

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

10. UNICEF Map of Fluorosis

11. Fluorosis in India
15 states

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. studies from our country

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. 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. 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. 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. 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. 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. 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. 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. 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. study from Europe

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. studies from china

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 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. 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.

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 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. 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
/- 7.75
/- 6.2
Urinary Iodine
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 Oct;15(5): [Effects of high iodine and high fluorine, Yang Y, Wang X, Guo X.

30. studies from Russia

31. 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) 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 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: 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 membrane
Edema and degeneration of the follicular epithelial cells.
Increased follicular vascularity.
Fatty degeneration in the inter-follicular connective tissue.
Vacuolations in the colloid

34. Empty Acinar Appearance

35. Pseudopodia Engulf Colloid
ELECTRON MICROGRAPH

36. biochemical basis

37. 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

38. 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.

39. Clinical aspects

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. 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

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. 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. Clinical Photographs

45. Higher Grades of Goitre

46. Mother with Grade IV Goitre
Her son with MR

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

48. Skeletal Fluorosis

49. Skeletal Fluorosis

50. Skeletal Fluorosis

51. Skeletal Fluorosis

52. Skeletal Fluorosis

53. Dental Fluorosis

54. Dental Fluorosis

55. 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

56. Resources Consulted Second Look – www.SLweb.org
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. Sukham Samagram Vijnane Vimale cha Pratishthitam
Our Obeisance
Sukham Samagram Vijnane Vimale cha Pratishthitam
All happiness is rooted in the Good Science
- Charaka Samhita

58. Thank You One and All