Transcript Fluorosis and Thyroid by Dr Sarma

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
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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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Resources Consulted
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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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Cause – Effect Relationship
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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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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
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Hormonogenesis
There are following 5 steps in the hormonogenesis
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Trapping inorganic Iodine from dietary Iodides
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Activation of Iodine to high valance I2
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Incorporation of I2 into Tyrosine of Thyroid Globulin
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Coupling of formed MIT and DIT to form T4 & T3
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Proteolysis of Thyroglobulin to release T4 & T3
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The Iodine Cycle
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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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T4 Catabolism
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What happens in Fluorosis ?
Normal catabolism -Thyroxine Abnormal catabolism -Thyroxine
FT4
T3
FT4
T3
rT3
rT3 will be LOW
rT3 ÷ T3 ratio will be LOW
Normal deiodination of T4
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rT3
rT3 will be HIGH
rT3 ÷ T3 ratio will be HIGH
Fluoride affects the normal
deiodination of T4
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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 and deep waters in
nine states in India.
• This is beyond the permissible limit
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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
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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
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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.
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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.)
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5. The Assam Story
1. 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
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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..
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/L
7. 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.
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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
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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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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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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 LowIodine 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
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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 LowIodine 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
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(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.
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Chinese Centre for Endemic Disease Control and Research, pp 120-125.
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13. Shandong Study
Parameter examined
Low I, High F area
Control area
Thyromegaly Adults
3.8%
<1%
Thyromegaly Children
29.8%
<5%
Dental fluorosis Adults
Dental fluorosis Child
35.48%
72.9%,
Absent
Low
Average I.Q of pupil
76.67 +/- 7.75
88.88 +/- 6.2
Urinary Iodine
Urinary Fluorine
Low
2.08 mg/l,
816.25 mcg/l
Low
I 131 uptake 3 and 24 h
9.36 and 9.26
High
Serum TSH levels
Higher
Normal
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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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14. Water Fluoride and Thyroid
Parameter examined
Clinical Diagnosis
Number of subjects
Group A
Healthy
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↑ fluorine content (122 +/- 5 T3↓ TSH↑,
mμmol/l of water
RAIU↑
normal F of 52 +/- 5 mμmol/l No change
in water
Group B
Hyperthyroid
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Group C
Hypothyroid
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Mild
improvement
Worsened
No change
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 .
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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 function
Ter Arkh. 1995;67(1):41-2. The thyroid and immune statuses of workers with long-term
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fluorine exposure : Balabolkin MI, Mikhailets ND, Lobovskaia RN, Chernousova NV.
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16. Industrial Fluorosis
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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.
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17. Fluorosis- Calcitonin
• Workers engaged in fluorine production were studied
• RIA of thyrotropin and thyroid hormones in the blood
• Moderate functional impairment of the hypophysisthyroid 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.
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Pathology
Effect of sodium fluoride on the thyroid glands
1. Depletion of colloid from the follicles.
2. Shrinkage of follicles.
3. Disruption of follicular basement membrane
4. 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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Fluoride may Affect
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Iodine pump, Peroxidase reactions
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Coupling reactions, Lysosomal hydrolysis
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Peripheral conversion of T4 to T3↓, Reverse T3↑
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Hypothalamic TRH causes TSH release from
thyrotroph using DAG/IP3/Ca2+ mechanism (Gq)
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TSH via cAMP (Gs/PKA) mechanism activates all
aspects of follicular cell thyroid hormone
synthesis, processing and release, as well as cell
growth
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Biochemical Basis
1.
TSH stimulation of thyroid Adenyl Cyclase (AC) is
absolutely dependent on the regulatory nucleotides,
the G proteins
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Sodium fluoride has dual actions on AC
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The AC activity increased as the concentration of
NaF increased from 0.01 to 1 mM,
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PFDA alters biochemical processes at cellular level
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Fluoride stimulation of Adenyl Cyclase (AC) activity
is two to three fold higher than that of TSH.
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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
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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
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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
• 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 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
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Future Research Needs
1. Methodologically rigorous studies on the cause effect
relationship of Fluorosis and Thyroid function
2. Multidisciplinary approach for such studies
3. The exact mechanism of thyroid functional
derangement needs to be elucidated
4. Combined clinico-epidemiological studies on
endemic fluorosis in areas of endemic goitre
5. Study on drugs which can modify fluoride toxicity
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Our Obeisance
Sukham Samagram Vijnane
Vimale cha Pratishthitam
All happiness is rooted
Science
in the Good
- Charaka Samhita
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