1Dr.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 98940 60593, (04116) 260593

2Dr.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.

3Dr.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

4Dr.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

5Dr.Sarma@works

PLASMA T4 to FT4

HYPOTHALAMUS -

TRHANT. PITUITARY - TSH

THYROID T4 and T3

PLASMA T3 to FT3

TISSUES T4 to T3, rT3

TSH -R

Thyroid Regulation

6Dr.Sarma@works

There are following 5 steps in the hormonogenesis

1. Trapping inorganic Iodine from dietary Iodides

2. Activation of Iodine to high valance I2

3. Incorporation of I2 into Tyrosine of Thyroid Globulin

4. Coupling of formed MIT and DIT to form T4 & T3

5. Proteolysis of Thyroglobulin to release T4 & T3

Hormonogenesis

7Dr.Sarma@works

The Iodine Cycle

8Dr.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).

9Dr.Sarma@works

T4 Catabolism

10Dr.Sarma@works

What happens in Fluorosis ?Abnormal catabolism -Thyroxine FT4 T3

rT3 will be HIGHrT3 ÷ T3 ratio will be HIGHFluoride affects the normaldeiodination of T4

rT3

Normal catabolism -Thyroxine FT4 T3

rT3 will be LOWrT3 ÷ T3 ratio will be LOWNormal deiodination of T4

rT3

11Dr.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 and deep waters in nine states in India.

• This is beyond the permissible limit

12Dr.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

13Dr.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.

14Dr.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 • In abundance of Iodine this does not occur• 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 in animal experiments

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.

15Dr.Sarma@works

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 with

high fluoride content of water and also dental fluorosis – the milder form of 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.)

16Dr.Sarma@works

5. The Assam Story1. It is colourless, odourless water that is wreaking havoc on

hundreds of thousands of people in many families in Assam. 2. Around 2,00,000 people are in the grip of hydro-fluorosis. 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. 5. In Karbi Anglong, one-seventh 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

17Dr.Sarma@works

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/L7. 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, 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

18Dr.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

19Dr.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

20Dr.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.

21Dr.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.)

22Dr.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.

23Dr.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.

24Dr.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.

25Dr.Sarma@works

Parameter examined Low I, High F area

Control area

Thyromegaly Adults 3.8% < 1 %Thyromegaly Children 29.8% < 5 %

Dental fluorosis Adults 35.48% AbsentDental fluorosis Child 72.9%, Low

Average I.Q of pupil 76.67 +/- 7.75 88.88 +/- 6.2

Urinary Iodine Low 816.25 mcg/lUrinary Fluorine 2.08 mg/l, Low

I 131 uptake 3 and 24 h 9.36 and 9.26 High

Serum TSH levels Higher Normal

13. Shandong Study

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.

26Dr.Sarma@works

Parameter examined Group A Group B Group CClinical Diagnosis Healthy Hyperthyroid HypothyroidNumber 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 No change No change

14. Water Fluoride and Thyroid

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 .

27Dr.Sarma@works

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 activity

declined, indicating impaired T helper functionTer 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.

28Dr.Sarma@works

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 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

– Moderate reduction of iodine-absorbing function of the thyroid, – 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.

29Dr.Sarma@works

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 parafollicular cells.

Gig Tr Prof Zabol. 1989(9):19-22. Chronic effects of fluorides on the pituitary-thyroid system in industrial workers, Tokar' VI, Voroshnin VV, Sherbakov SV.

30Dr.Sarma@works

PathologyEffect of sodium fluoride on the thyroid glands1. Depletion of colloid from the follicles. 2. Shrinkage of follicles. 3. Disruption of follicular basement membrane4. Edema and degeneration of the follicular

epithelial cells.5. Increased follicular vascularity. 6. Fatty degeneration in the inter-follicular

connective tissue. 7. Vacuolations in the colloid

31Dr.Sarma@works

1. Iodine pump, Peroxidase reactions

2. Coupling reactions, Lysosomal hydrolysis

3. Peripheral conversion of T4 to T3↓, Reverse T3↑4. Hypothalamic TRH causes TSH release from

thyrotroph using DAG/IP3/Ca2+ mechanism (Gq)

5. TSH via cAMP (Gs/PKA) mechanism activates all aspects of follicular cell thyroid hormone synthesis, processing and release, as well as cell growth

Fluoride may Affect

32Dr.Sarma@works

Biochemical Basis1. 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 NaF increased from 0.01 to 1 mM,

4. PFDA alters biochemical processes at cellular level

5. Fluoride stimulation of Adenyl Cyclase (AC) activity is two to three fold higher than that of TSH.

33Dr.Sarma@works

FluorosisFluoride 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.

34Dr.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

35Dr.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

36Dr.Sarma@works

Diagnostic Tests• FT4, TSH to diagnose clinical & sub-clinical hypo function• FT3 to identify low T3 syndrome, rT3 and T3/rT3 ratio• Sialic Acid in plasma and urine, urinary fluoride excretion• Drinking water sample analysis for fluoride levelsChronology of Thyroid Function Test abnormalities

1. 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

37Dr.Sarma@works

Future Research Needs1. Methodologically rigorous studies on the cause effect

relationship of Fluorosis and Thyroid function2. Multidisciplinary approach for such studies3. The exact mechanism of thyroid functional

derangement needs to be elucidated4. Combined clinico-epidemiological studies on endemic

fluorosis in areas of endemic goitre5. Study on drugs which can modify fluoride toxicity

38Dr.Sarma@works

Our Obeisance

Sukham Samagram Vijnane Vimale cha

PratishthitamAll happiness is rooted

in the Good Science - Charaka Samhita