Fluorosis And THYROID

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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, [phone]

2
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.

3
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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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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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
• 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

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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 gt Bromine
  gt 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 ?
Abnormal catabolism -Thyroxine FT4
T3 rT3 will be HIGH rT3 T3 ratio
will be HIGH Fluoride affects the
normal deiodination of T4
Normal catabolism -Thyroxine FT4
T3 rT3 will be LOW rT3 T3 ratio will
be LOW 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 lt 0.01
• Goitre prevalence v/s fluoride content - P lt 0.01
• Goitre prevalence v/s hardness - P gt 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. 26187-90.
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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
• 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
181102-1110. Effect of fluorine on thyroid
metabolism in hyperthyroidism - PIERRE-M.
GALLETTI, M.D., PH.D AND GUSTAVE JOYET, D.Sc.
15
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

Health News, India Fluoride in water takes its
toll in Assam
A SPECIAL FEATURE ARTICLE ON
23-June-2004
17
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.

Health News, India Fluoride in water takes its
toll in Assam
A SPECIAL FEATURE ARTICLE ON
23-June-2004
18
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 lt 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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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.)
22
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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13. Shandong Study
Parameter examined Low I, High F area Control area
Thyromegaly Adults 3.8 lt 1
Thyromegaly Children 29.8 lt 5
Dental fluorosis Adults 35.48 Absent
Dental fluorosis Child 72.9, Low
Average I.Q of pupil 76.67 /- 7.75 88.88 /- 6.2
Urinary Iodine Low 816.25 mcg/l
Urinary Fluorine 2.08 mg/l, Low
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. 1994
Oct15(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 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 No change No change
Probl Endokrinol (Mosk). 1985 Nov-Dec31(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. 199567(1)41-2. The thyroid and immune
statuses of workers with long-term fluorine
exposure Balabolkin MI, Mikhailets ND,
Lobovskaia RN, Chernousova NV.
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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.
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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
  hypophysis-thyroid gland system without overt
  hypo thyroidism
• Elevation of calcitonin concentration indicated
  stimulation of thyroid glands 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
• 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

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Fluoride may Affect

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

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Biochemical Basis

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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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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UNICEFs 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

• 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 in the Good
Science - Charaka Samhita