Division Of Cancer Epidemiology And GeneticsRadiation Epidemiology Branch

Non Malignant Thyroid DiseasesNon-Malignant Thyroid Diseases Following a Wide Range of

Radiation Exposures

Elaine RonAlina BrennerAlina Brenner

Late Health Effects of Ionizing Radiation:Late Health Effects of Ionizing Radiation: Bridging the Experimental and Epidemiologic Divide

May 4-6, 2009

OutlineOutline

• A little thyroid gland biologyA little thyroid gland biology• Radiation effects

– Nodules– Hyperthyroidism

H th idi– Hypothyroidism– Autoimmune thyroiditis or elevated levels of

antibodiesantibodies

• Conclusions

Thyroid GlandThyroid Gland

• Makes and storesMakes and stores thyroid hormones

• Thyroid hormonesThyroid hormones instrumental in regulating growth, g g g ,metabolism, reproduction, tissue f ifunction

Thyroid Gland20

30

ve ri

sk Thyroid Gland0 1 2 3 4 5

0

10

Dose (Gy)

Rel

ativ

Age at exposure: < 15: >= 15:

• Radiation effects first reported in 1920s• 1950s clinical observations of association

between external radiation and thyroid cancer

• One of the most radiosensitive organs• Strong linear radiation dose response for g p

cancer especially after childhood exposure• Limited information on radiation and otherLimited information on radiation and other

thyroid diseases

Th id DiThyroid Diseases

Structural Functional• Tumors

– Malignant• Hyperthyroidism• Hypothyroidism

– Benign

• NodulesHyperplastic*

• Autoimmune thyroiditis• Elevated levels of – Hyperplastic

– Cyst

• Thyroid enlargement

antibodies

* Includes nodular goiter

Thyroid Nodule Diagnosis in T itiTransition

• Cancer is a very smallCancer is a very small proportion of nodules

• In past, follicular adenomas defined as benign tumors and most other nodules not considered neoplasticconsidered neoplastic

• Recently, definition of benign nodules reconsidered based on clonal origin

• Difficult to make differential di i t di

Eszlinger et al. JCEM, 2008diagnosis, so many studies combine all benign nodules

Data Sources• Medical

– Children treated with radiation for– Children treated with radiation for benign diseases

– Children and adults treated with radiation for cancer

• Environmental– Chernobyl– Nevada and Kazakhstan test sites

Hanford and Mayak nuclear weapons– Hanford and Mayak nuclear weapons facilities

– Marshall Islanders

• Atomic bomb survivors (AHS)

Thyroid Nodules

Lower Risks for Follicular Adenoma Versus Thyroid Cancer

Ti C iti P ti t Uk i NCI Ch b l

Tumor ERRG

Tinea Capitis PatientsIsrael

Tumor ERRG

Ukraine-NCI Chernobyl Screening Study

Tumor type Cases ERRGy

(95% CI)

Malignant 159 20(12 32)

Tumor type Cases ERRGy

(95% CI)

Malignant 45 5.25(1 7 27)a g a t 59 (12,32)

Follicular adenoma* 42 8

(7,10)

a g a t 5 (1.7, 27)Follicular adenoma* 23 2.07

(0.3, 10)( )

Ratio: malignant/benign = 2.5

( )

Ratio: malignant/benign = 2.5

*b d th l i f t ti

Sadetzki et al. JECM, 2006Ron et al. Rad Res, 1989

Tronko et al. JNCI, 2006Zablotska et al. AJE, 2008

*based on pathology review of tumor tissue

But, for total nodules less clear

Michael Reese Hospital C h t St d

Atomic Bomb

Tumor type Cases ERRGy

(95% CI)

Cohort StudyTumor type Cases EORSv

(95% CI)

Survivors (AHS)

type (95% CI)

Malignant 309 3.0(0.1, 4.0)

type (95% CI)

Malignant 70 1.95(0.67, 4.9)

Benign nodules* 549 8.0

(0.3, 3.7)Benign nodules* 156 1.53

(0.76, 2.7)

Ratio: malignant/benign =0.38

*includes follicular adenoma and other nodules

Ratio: malignant/benign =1.28

Imaizumi et al. JAMA, 2006

*includes follicular adenoma and other nodules

Schneider et al. JECM, 1993

Nodules Associated with High-gDose Radiotherapy for Childhood

Hodgkin DiseaseHodgkin Disease• Thyroid doses ten’s of Gy (Mantle

field)field)• 20-40% risk of developing thyroid

nodulesMantle

• Based on small numbers– Risk of radiation-related benign nodule

slightl lo er than for malignant

field

slightly lower than for malignant– Age, gender and follow-up patterns

similar to cancer patterns

Von der Weid. Support Care Cancer, 2008Acharya et al. Cancer, 2003

Nodules Associated with High-Dose Radiotherapy for Childhood

Hodgkin Diseaseodg sease• Study population

– 146 patients who developed nodules among 1,791 members of CCSS

– 79% had radiotherapy79% had radiotherapy – median thyroid dose, 35 Gy; maximum 55 Gy

• Relative Risks – compared to siblings = 27 (P <0.001) – at >25 Gy = 2.9 (1.4, 6.9)

Sklar et al. JECM, 2000

Thyroid Nodules and Radioactive yIodine Exposure from Fallout

N d S i l ti kNevada Weapons Test Site

• 2500 study subjects

SemipalatinskWeapons Test Site

• 3000 study subjects• Mean dose 120 mGy• Benign tumors (n=15)

y j

• Mean dose: 40 mGy

external; 300 mGy internalERRGy not estimated, Ptrend

<0.001 • Total nodules (n=54)

; y• Total nodules (n=916)

increased with dose, Ptrend• Total nodules (n=54)ERRGy = 4.65; (CI 1.1, 12.3)

<0.001• EORGy = 0.74 (CI 0.22, 1.24)

Lyon et al. Epidemiol, 2006 Land et al. Radiat Res, 2008

Benign Nodules and En ironmental I 131Environmental I-131

• Marshall Islands fallout– High doses on Rongelap, Ailinginae and Utrik

• Clear increase of nodules Low doses on other islands– Low doses on other islands

• Results inconsistent and not well quantified• Inverse relationship - nodules and distance from test site

(Hamilton et al 1987)(Hamilton et al 1987)• Positive relationship - nodules and distance from test site

(Takahashi et al 2001)

• Ozyorsk (Mushkacheva et al 2006)Ozyorsk (Mushkacheva et al 2006)

– Nodules (n=165); RR= 1.4 (CI 1.0, 1.9)• Hanford Nuclear Site (Davis et al 2004)Hanford Nuclear Site (Davis et al 2004)

– Nodules (n=249); ERRGy= -0.008 (CI <-0.02, 0.04)

Functional Thyroid T3Functional Thyroid Diseases

• Excess or deficit of blood levels of thyroid hormones (T4 T3 TSH) alonethyroid hormones (T4, T3, TSH) alone or in combinationC i i ti ith th id• Can occur in association with thyroid nodules

T4

Hyperthyroidism FollowingHyperthyroidism Following High-Dose Radiotherapy

• Overactive thyroid– Thyroid produces too much thyroxine (T4)– Pituitary produces too little TSH

• Relatively rare• Reported infrequently following

radiotherapy for Hodgkin disease in adults, adolescents and children

• Most studies small and do not have individual doses

Hyperthyroidismyp yAtomic Bomb Survivors CCSS

P b bilit f d l i(AHS) Probability of developing hyperthyroidism by dose

4091 i

1791 survivors 2808 siblingsP =0 1010-

4091 survivors51 cases

1791 survivors, 2808 siblings82 cases; 13 control casesRR = 8.0 (4.6, 15)

ds R

atio

P =0.108-6-4-2-

Od

0-

Sklar et al. JCEM, 2000Imaizumi et al. JAMA, 2006

Thyroid Dose, Sv

Hypothyroidismyp y• Underactive thyroid

– Thyroid doesn't produce enough thyroxine (T4) – Pituitary produces too much TSH in an attempt to

compensatep

• Most common thyroid disease– Overt (low T4, normal TSH) - requires treatmentOvert (low T4, normal TSH) requires treatment– Subclinical (high TSH, normal T4) - sometimes treated

• A known late effect of high-dose exposureg p• Effects after low or moderate doses less clear

– Lack of individual doses– Lack of individual doses– Study design

Hypothyroidism following High-Dose R di th i Childh dRadiotherapy in Childhood

• 1,791 members of CCSS; 2808 ;siblings

• 456 CCSS cases;• 456 CCSS cases; 39 control cases

• RR = 17.1 (12, 24), p<0.0001

Probability of developing

Sklar et al. JCEM, 2000

Probability of developing hypothyroidism by thyroid dose

Mild Hypothyroidism and I-131 Dose from Chernobyl Accident

Ukraine-NCI Thyroid

3 0

3.5Category specific ORsFitted ORs based on linear EOR mo

EORGy = 0.10 (95%CI: 0.03; 0.21)

• Category specific ORFitted ORs based on linear model

Ukraine-NCI Thyroid Screening Study

• 11,853 people <18 yrs at accident

2.0

2.5

3.0

OR

__ Fitted ORs based on linear model

OR

• Individual thyroid measurements;– mean thyroid dose = 0.79 Gy; range, 0-

40.7

1.0

1.5

2.0O O • Clinical exam including lab tests• 719 cases with hypothyroidism

– TSH > 4 mIU/L

0.50.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0

Thyroid dose, GyThyroid Dose

– TSH > 4 mIU/L

• Significant relation between prevalence of hypothyroidism and 131I dose from environmental

Ostroumova et al. EHP, in press

I dose from environmental exposure

See Poster by M. Hatch

HypothyroidismHypothyroidismDefinite Effect Possible Effect

• Irradiated cancer patients

• Chernobyl residents• Nevada Test Site

• I-131 treated hyperthyroid

Nevada Test Site• Atomic bomb

survivors (AHS)patients

• Marshall Islanders

survivors (AHS)

No EffectH f d• Hanford

Autoimmune Thyroiditis (AIT)Autoimmune Thyroiditis (AIT)• Relatively common

E k l ti hi ith I 131 lt i• Even a weak relationship with I-131 may result in significant morbidity – hormone replacement to treat thyroid failure or preventhormone replacement to treat thyroid failure or prevent

cardiovascular complications– could increase risk of thyroid cancer

• Various clinical manifestations and degree of thyroid• Various clinical manifestations and degree of thyroid dysfunction

• No internationally accepted classificationNo internationally accepted classification– High thyroid antibodies, ATPO ≥ 250 U/ml– High thyrotropin, TSH ≥ 10.0 mIU/L– Ultrasound, heterogeneous and hypoechoic

Prevalence of AIT and I-131 DoseUkraine-NCI Screening Study

Thyroid dose GyAIT Thyroid dose, Gy<0.14 0.14- 0.34- 0.66- 0.96- 1.5- 3+

Cases 65 50 41 14 10 15 9Cases 65 50 41 14 10 15 9

Non-cases 3,938 2,776 1,906 812 727 998 530

OR*95% CI

1.0 1.10.8,1.7

1.30.8,1.9

1.20.7,2.2

1.10.6,2.0

0.70.4,1.5

0.90.4,1.9

Ptrend = 0.25

*Adjusted for family history of thyroid disease, smoking, thyroid volume, presence of nodules, serum Tg, sex and age

Tronko et al. JCEM, 2006

Anti-Thyroid AntibodiesStudy (reference) Subjects End points ResultsUtah, Nevada, Arizona

Kerber et al, 1993Lyon et al, 2005

2,4732,497

AMA, ATG, TSHAMA, ATG, TSH

Null Positive

A-bomb survivors (AHS)A-bomb survivors (AHS) Nagataki et al, 1994Imaizumi et al, 2006

2,5874,091

AMA, ATG, TSHATPO, ATG, TSH

PositiveNull

Marshall IslandsTakashi et al, 1999* 4,766 AMA, ATG, TSH Null

HanfordHanfordDavis et al, 2004 3,440 AMA or ATPO, Null

Western PomeraniaV lt k t l 2005* 4,299 ATPO, US PositiveVoltzke et al, 2005* , ,

*No individual doses

Prevalence of ATPO and I-131 DoseUkraine-NCI Screening Study

ATPO iti l l t dATPO positively related to dose

D i t t2.02.12.22.3

OR=dose0.08

OR=(1+0.68*dose*e-0.60*dose)

– Dose response consistent with linear-exponential or power model

1 11.21.31.41.51.61.71.81.9

OR

, 95%

CI

– Dose response not driven solely by people with high ATPO levels

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.00.70.80.91.01.1

Thyroid dose, Gy

– ATPO dose response not due to other thyroid disordersdisorders

Tronko et al. JCEM, 2006

Mechanisms for Radiation-InducedMechanisms for Radiation-Induced Thyroid Nodules

• Thyroid cancer – Papillary: chromosomal rearrangementsp y g– Follicular: point mutations

• Benign Nodulesg– Mechanism unknown– Speculation: nodules often have a p

follicular component, so possibly point mutations involved

Mechanisms for Radiation-InducedMechanisms for Radiation-Induced Thyroid Dysfunction

• Direct thyroid cell injury or death• Prevention of cell division• Immune-mediated damageImmune mediated damage• Inflammatory reaction• Damage to small thyroid vessels and• Damage to small thyroid vessels and

gland capsule

ConclusionsConclusions

Si ifi t d fSignificant dose-response for benign nodules – Dose-response appears to be linear– May be somewhat weaker than for

li t tmalignant tumors– Age and latency patterns similar

Conclusions• Data on hyperthyroidism sparse, but

suggestion of an elevated risk in a few high-dose radiotherapy studieshigh-dose radiotherapy studies

• Overt hypothyroidism observed after high-dose radiotherapy; dose-response g py; prelation

• Subclinical hypothyroidism, autoimmune th roiditis and/or ele ated ATPO mathyroiditis and/or elevated ATPO may occur at lower doses, but– Results are inconsistent– Shape of the dose response is unclear – Some of the effects may be transient

• Data not sufficient to describe effect ata ot su c e t to desc be e ectmodification for any outcome