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OUTLINE

Introduction
Autoimmunity-Concept
Environmental factors affecting thyroid
Description
Smoking
Micronutrients
Iodine
Selenium
Thiocynate

Drugs

Amiodarone
Lithium
Interferon alpha
TKI

Infections
Radiation
Pollutants

Summary

INTRODUCTION
Environmental factors triggers thyroid
autoimmunity (TAI) in genetically susceptible
individuals.
TAI autoimmunity and dysfunction can present
with hypothyroidism or hyperthyroidism.
Background incidence of thyroid autoimmunity in
India.

Hypothyroidism
Overthypothyroidism3.9%
SubclinicalhypothyroidismM/F11.4/6.2%
53%SCHhave+TPOAb

Hyperthyroidism
Overt-1.3%
Subclinical hyperthyroidism1.6

U Menon et al;J Indian Med Assoc. 2009.

Thyroid diseases-Interaction of the environment, gene and thyroid


Genetic factor
contributes-70-80%
Environmental factor
contributes-20%

AUTOIMMUNITY MODEL

Nature reviews of immunology;2014

AUTOIMMUNITY-MOLECULAR

Nature reviews immunology;2014

SMOKING
Graves disease
Increases the risk of Graves disease occurrence (Hagg et
al).
Decreases the chance of remission of hyperthyroidism .
Smoking alters natural history of GO
More frequent,
More severe
Less responsive to medical treatment

Hashimoto thyroiditis
Negative association with TPOAb and TgAb.
Negative association with hypothyroidism
? Protective effect

CSE acts through the cytokines

Smoking increases the HA

CSE increases the IL-1. IL-1 synergistically increases the adipogenesis


along with CSE.

MICRONUTRIENTS
S M A L L M O L E C U L E , B I G I M PA C T

Environment
Goiter was more common in
Smoker
Women with high parity
Goiter was less common in
Alcoholism
OCP user

Aalborg
SEX

Copenhagen

Male FEMALE Male


Female

Low TSH

11.1%

7.2
%

8.3%

4.0%

Increased TSH

8.2%

2.1

9.1%

2.7%

Prevalence of one or both antibodies -18.8%.


Prevalence rates of the two antibodies (TPO-Ab / Tg-Ab): 13.1/13.0%).
More common in women than in men.
Prevalence increased with age.
TPO is strong predictor than Tg-Ab.

SOURCES OF IODINE

Iodine-containing drugs
Cough syrups-Iodine containing
Povidone-Iodine, used for topical disinfection.
Seaweed preparations containing up to 2 mg iodine per
gram in protein-bound form available
Contrast agents for conventional radiography or
computer tomography.
Erythrosine (food additive E127) containing 57% iodine
and used, for example, to improve the colour of canned
cherries or of candies.
Iodised salt; (over-iodised by inadvertence).

Aim --to correlate iodine intake, thyroid autoimmunity, and recognition of


thyroglobulin (Tg) epitopes after implementation of iodine prophylaxis.
Main Outcome Measures:

Thyroglobulin autoantibodies (TgAb), thyroperoxidase autoantibodies (TPOAb),


and urinary iodine excretion were assessed in 906 iodized salt users (IS-users)
and 389 nonusers (IS-nonusers).

Ultrasound (US) was performed to identify thyroid hypoechogenicity, sug- gestive


of Hashimoto thyroiditis (HT).

Frequency of positive Tab was much higher in HT-US than in non-HT-US (59/87, 67.8% vs 233/1208, 19.3%, P< .
0001)
TgAb (45/87, 51.7% vs 179/1208,14.8%, P<.0001)
TPOAb (55/87, 63.2% vs 149/1208, 12.3%, "2 " 158.3, P <0001)

In HT-US subjects, serum levels of TgAb were also significantly higher in IS-users than
in IS-nonusers (median, IQR: 108 U/mL, 8501 U/mL vs 0 U/mL, 053 U/mL; P " .02)
Serum levels of levels of TPOAb were not significantly different between the two
groups (161 U/mL, 0588 U/mL, vs 0 U/mL, 0434 U/mL)

Inhibition by region B TgAb-Fab was significantly higher in IS-users (27.5%,


6.548.3%) than in IS-nonusers (3.0%, 0.020.5%) (P .047).

SELENIUM

Objective- To see effect of the selenium on the thyroid.


Comparison was done between Ziyang (Adequacy Se country, Soil
Se 30 mg/kg and Ningshan (Low Se country 0.17 mg/kg).

Ningshan

Ziyang

Higher serum selenium was associated with


Lower odds ratio (95%confidence interval) of autoimmune thyroiditis
(0.47; 0.35, 0.65),
Subclinical hypothyroidism (0.68;0.58, 0.93),
Hypothyroidism (0.75; 0.63, 0.90),
Enlarged thyroid (0.75; 0.59, 0.97)

Participants were divided into quintiles


by serum Se:
Q1 (quintile 1) 47.00 ug/L;
Q2 (quintile 2), 47.0068.99 ug/L;
Q3 (quintile 3) 69.0090.99 ug/L;
Q4 (quintile 4) 91.00119.99 ug/L,
Q5(quintile 5) 120.00 ug/L.

In the whole population, the prevalence of overt hypothyroidism,


subclinical hypothyroidism, autoimmune thyroiditis, and enlarged
thyroid was highest in the bottom quintile of serum Se ( 47 ug/L).
The prevalence of hypothyroidism, subclinical hypothyroidism, and
autoimmune thyroiditis decreased as serum Se concentration rose from
the bottom to the third quintile above which it reversed or attenuated.

Lacto peroxidase based methods were used to retard bacterial


growth of the bacteria in the milk.
SCN was by product of this reaction.

AMIODARONE
Amiodarone
benzofuran derivative
two iodine atoms per molecule
37% iodine by weight

With dose of 100 mg, 13 mg


of iodine (BA-40%) will be
delivered.
With Vd of 60
l/lipophilic/very long half
life (40 days).
Act as thyroid hormone
analog in pituitary and liver.

PATHOPHYSIOLOGY OF THE DRUG


EFFECT
Iodine reated effects

WolffChaikoff effect
JodBasedow effect

Direct effect of the drug

Inhibition of D1 activity in peripheral


tissues by amiodarone metabolites.
Decreased intracellular T4 transport.
Decreased expression of the LDLR
(psuedohypothyroid pattern).
Direct dose dependent folliculotoxic
effect.

AMIODARONE INDUCED
HYPOTHYROIDISM
Prevalence-1020% (Short term), 5-10% (1 year)
more frequent in iodine-sufficient areas.
Incidence ratio (W:M)- 1.5:1.
Thyroid autoantibodies increase likelihood of
developing AIH.
OR X 14 (F/+Tab).
Symptoms of hypothyroidism (Classical plus)
Torsades de pointes
Acute kidney injury (Reversal with LT4 supplement)

Patient with TSH >10 mu/l should be treated.


May improved after stopping the amiodarone

AMIODARONE INDUCED
THYROTOXICOSIS

Prevalence=5-10%.
The M:F incidence ratio is 3:1.
The time of onset of AIT is less predictable.
When to suspect?
Reappearance or exacerbation of the under lying cardiac
disorder after amiodarone treatment.
Deranged warfarin sensitivity.

Can present with minimal symptoms


Antiadrenergic effects.(no adrenergic symptoms)
Less T4 to T3 conversion. (High T4 can be found normally with
amiodarone)

Feature

Type 1 AIT

Type 2 AIT

Underlying thyroid disease

Yes

No

Thyroid antibody

Yes

Usually no

Pathogenesis

Iodine induced
hyperthyroidism

Thyroiditis

Histopathology

Follicular hyperplasia

Follicular damage, Fibrosis,


epithelia atrophy

Thyroid USG

Diffuse or nodular goiter

Small hypoechoic goiter

CFDS

Increased vascularity

Decreased vascularity

Thyroidal RAIU

Increased/Low/Decreased

Decreased (<1%)

MIBI

Thyroid retention

Decreased/Absent

Spontaneous remission

No

Possible (20%)

Preferred medical therapy

Thionamides
(KClo4)

Glucocorticoids

Subsequent hypothyroidism

Unlikely

Possible

Subsequent therapy for the


underlying thyroid disease

Likely

No

Increased dose of the


Thionamides may be
required.
If uptake is >10%
may require
surgery/RAI

40 to 60 mg/day
of prednisolone
for 1 to 3 month

Stopping amiodarone may worsen the cardiac status in the AIT

EFFECT OF LITHIUM ON THYROID


Increased IGF-1
Increased RTK activity
Increased beta-catenin
activity

Increased TSH response to TRH


Decreased down stream c AMP
pathway

Alters the T3 to TR
binding
Alters TR to DNA binding
Alters ITDI (decrease 2,
increase 3)

Inhibit tubule polymerization

Compete with iodine for NIS


Hypothyroidism
Reduced RIA

GOITER
Goiter occur in 5-30% of subjects
More common in female
Diffuse>Nodular
More common with longer duration of treatment
More common with prior antibodies
50% to 70% with USG (so USG recommended)

Levothyroxine is recommended
Very large goiter
Cosmetic/compressive
TSH >10 mu/L

Target-T4 normal/just above normal, T3 normal,


TSH-normal range.
JHLazarus;BestPractice&ResearchClinicalEndocrinology&Metabolism23(2009)

LITHIUM INDUCED HYPOTHYROIDISM

Prevalence ranges from 3 to 23%.


Incidence 1.5% year
F:M ratio 5:1.
Age > 50 year, female gender (OR-5.9), + family
history, iodine status and + TAb are main risk factors.
Hypothyroidism can be autoimmune and non
autoimmune.
Preexisting uncontrolled hypothyroidism can lead to
lithium toxicity.

Lazarus; Thyroid 1998

LITHIUM INDUCED HYPERTHYROIDISM


Prevalence-1.5 to 3 cases per 1000 person.
Silent painless thyroiditis are main cause of
the thyrotoxicosis.
Granulomatous thyroiditis, lymphocytic
thyroiditis or non-specific thyroiditis are
other causes.
Graves disease is rare.
Lithium can mask the thyrotoxicosis due to
its own effect.
Lazarus;BestPractice&ResearchClinicalEndocrinology&Metabolism23(2009)

INTERFERON
Thyroid dysfunction can be found in the 25 to
40% of the patients.
Can be divided into
Autoimmune
Graves disease
Hashimoto thyroiditis
Asymptomatic disease

Non autoimmune
Destructive thyroiditis
Non autoimmune hypothyroidism

CHARACTERISTICS OF THE PATIENTS

TYROSI
NE
KINASE
INHIBIT
ORS
TOXIC
EFFECT
OF
TARGET
ED
THERAP
Y

INFECTIONS

INFECTIONS
HEPATITIS C
The frequency of abnormally high
levels of antithyroid antibodies in
HCV-positive patients varies from
8% to 48%.
Spectrum of thyroid dysfunction
Thyroiditis
Hyperthyroidism
Thyroid cancer

Have both direct and indirect


effects.

Antonelli et al; Nature reviews of endocrinology;2009

CXCL-10 PRIME FACTOR FOR THE AITD

HEPATITIS WITH AITD

Am J Med.2004;117

HEPATITIS C AND THYROID CANCER

RADIATION
I N V I S I B L E E N E R GY , V I S I B L E E F F E C T S

Lancet;1998

Prevalence of positivity for antithyroglobulin and antithyroperoxidase in


individuals from Hoiniki and Braslav, in relation to the age at the time of
the accident (1986)
(p=004 vs 12 years; p=002 vs 35 years; p=001 vs 68 years)

POLLUTANTS

POLLUTANTS

Symbols:AandBsignificantdifferencesbetweengroupswithAandthosewithBwithinthesame
area(thelevelofsignificanceindicatedinthetext).
CorDp<0.01orp<0.001,respectively,betweengroupswithCorDinpollutedareaandgroups
withappropriatenumberinbackgroundpollutionarea.

Chemosphere;2007

TAKE HOME MESSAGE


AITDs result from a complex interplay among
genetic and environmental factors.
The most important model for this is iodine.
Environmental factors can lead to both hypo and
hyper functioning of the thyroid gland.

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