1 Dr.Sarma@works. 2 Fluorosis AND THYROID Dr.R.V.S.N.Sarma, M.D., M.Sc., (Canada) Consultant Physician & Chest Specialist President - IMA Tiruvallur Branch.

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FluorosisAND 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

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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.

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FLOURIDE

Thyroid is the battle ground

F and I in Fight

IODINE

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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).

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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

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PLASMA T4 to FT4

HYPOTHALAMUS -

TRH

ANT. PITUITARY - TSH

THYROID T4 and T3

PLASMA T3 to FT3

TISSUES T4 to T3, rT3

TSH -R

Thyroid Regulation

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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

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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

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UNICEF Map of Fluorosis

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Fluorosis in India

15 states

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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

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studies from our country

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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

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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.

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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.

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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.)

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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

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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

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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

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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

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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.

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study from Europe

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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.)

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studies from china

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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.

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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.

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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.

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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.

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studies from Russia

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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 .

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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.

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Pathology

Effect 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

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Empty Acinar Appearance

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Pseudopodia Engulf Colloid

ELECTRON MICROGRAPH

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biochemical basis

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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

Hormonogenesis Affected

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Adenyl Cyclase (AC)

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 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.

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Clinical aspects

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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.

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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

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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

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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 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

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Clinical Photographs

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Higher Grades of Goitre

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Mother with Grade IV Goitre Her son with MR

Grade IV Goitre

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Multinodular Gr IV Goitre

Multinodular Gr IV Goitre

Goitre in Himalayan belt

Grade IV Goitre

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Skeletal Fluorosis

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Skeletal Fluorosis

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Skeletal Fluorosis

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Skeletal Fluorosis

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Skeletal Fluorosis

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Dental Fluorosis

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Dental Fluorosis

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Summary

1. Fluorosis negatively affects Thyroid function 2. This association is seen in many studies from our country

as well as others3. Effects may range from simple goitre, sub clinical

hypothyroidism to frank hypothyroidism4. FT3, rT3 and rT3/T3 ratio need to be estimated in addition

to FT4 and TSH5. Sialic acid levels will be decreased in fluorosis6. ↑ Adenyl Cyclase (AC) through G reg. protein - mechanism7. In our country we need to be vigilant – both are endemic

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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

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Our Obeisance

Sukham Samagram Vijnane Vimale cha

PratishthitamAll happiness is rooted

in the Good Science - Charaka Samhita

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Thank You One and All