Goiter: Pathophysiology and clinical aspects Joaquín Lado Abeal, MD, PhD Department of Internal Medicine TTUHSC-SOM, Lubbock.

Goiter: Pathophysiology

and clinical aspects

Joaquín Lado Abeal, MD, PhD

Department of Internal Medicine

TTUHSC-SOM, Lubbock

Iodine intake(goitrogens)

Gender

Genetic

From Iodine Satus Worldwide. WHO Global Data Base on Iodine Deficiency. 2004

From Iodine Satus Worldwide. WHO Global Data Base on Iodine Deficiency. 2004

San Bartolomeu da Mota (A Mota, Arzua, Galicia)

Dr Gregorio Maranon

CRETINISM

Neurological Myxedematose

T3T4

TSH

Hyperthyrodism

High T4/T3Low TSH

Hypothyrodism

Low T4/T3High TSH

Thyroid Hormone Synthesis

TSH

Diferentiation Proliferation

Insulin/IGF-I

Pituitary TSHoma

TSH

Graves-Basedow disease

TSHR mutations

November 2001

May 2003

Syndrome of Resistance to Thyroid Hormone Action (SRTH)TS

H (m

U/L

)

Number of days

0

50

100

150

200

250

TG (µ

g/L)

6005004003002001000

0

5

10

15

150 200 250L-T3 dose µg c.2.d.

31

323334

353637

6005004003002001000

30Nec

k di

amet

er (

cm)

49

4547

51

Wei

ght (

Kg)

TT4

(µg/

dl)

0.1

1

2

0.05

0.5

N Range Mean SE p p

Euthyroid (Buenos Aires) 20 2.4-3.6 3.2 0.4

Non goiter (Neuquen) 14 2.4-5.6 4 0.8 <0.01

Goiter, grade I & II 6 3.2-5.6 3.6 0.8 NS NS

Goiter, grade III 8 2.4-5.6 4 0.8 <0.05 NS

Goiter, grado I & II 7 2.4-4.8 4 0.8 <0.05 NS

Goiter, grado III 5 2.8-7.2 4 0.8 <0.05 NS

TSH (µU/ml)

MA Pisarev, RD Utiger, JP Salvaneschi, N Altschuler, LJ DeGroot. Serum TSH and thyroxine in Goitrous Subjects in Argentina. J Clin Endocr. 30:680-681. 1970.

28.1.04 11.4.05 30.8.05

TSH µU/ml 0.42 0.10 0.08

FT4 ng/dl 1.08 0.88 0.80

FT3 pg/ml 3.29 3.89 3.65

NORMAL

0.35-5.50

0.85-1.86

2.20-4.70

MULTINODULAR GOITER

Ab TPOAbTG

< 33< 100

Pendred Sydrome

50 µg/day T4 (starting March 04)

100 µg/day T4 (starting Nov 04)

100 µg/day T4 Post surgery

(starting February 05)

Total Thyroidectomy(February 05)

27.11.03 28.05.04 2.02.05 4.03.05 Rango

Normal TSH, µUI/ml FT4, ng/dl FT3, pg/ml Tg Anti-TPO Ab Anti-TG Ab IGF-1, ng/ml Yoduria µg/L

3.29 0.51 3.78

153

1.99 0.77

1312 <10 <20

0.12 0.91 3.36

100 102

6.39 1.25

0.35-5.50 0.85-1.86 2.20-4.70 <35 <40 81-267 25-450

T4

rT3

T3

T4

D1, D2

D3

T4

T3

p.R277X / c.6205+1delG

WT/p.R277X

R277X

Red=goiterc.6205+1delG

WT/c.6205+1delG

WT / WT WT/c.6205+1delG

p.R277X / c.6205+1delG

p.R277X / c.6205+1delG

p.R277X / c.6205+1delG

T GTAAGTTCATTGTAAGTTCATTG

wildtypemutant

c.886C>Tp.R277X

c.6205+1delGExon 35 skipping

T

Exon 35 Intron 35

THYROGLOBULIN GENE MUTATIONS

Exon 7

WT/c.6205+1delG

Exon 34 Exon 36

Exon 35 skipping

K P M S L

TT GCT CAA AAT AAT GCT CCC AGT TTT TGC CCT TTG GTT GTT CTG CCT TCC CTC ACA GAG AAG I A Q N N A P S F C P L V V L P S L T E K

p.R277X /c.6205+1delG WT /c.6205+1delG

Thyroglobulin mutations

Goiter

defective hormone synthesis

high serum TSH

unfolded protein response

apoptosis

p53, NF-kB, MPAKs, VEGF

Cancer

BRAF mutations

oxidative stress

Afrikaner cow

1 48

9TG

INACTIVE

GDP

ACTIVE

GTP

GEF

GTPGDPGAP

Pi

RAS

R Wetzker, Frank-D Bohmer. Transactivation joins multiple tracks to the ERK/MAPK Cascade. Nature Reviews. Molecular Biology. 4: 651-657. 2003.

PLCDAG

PKC

RAS GTP

RalGDS Raf PLC PI3K

Ral

ProliferationCell survival

MEK

ERK

Proliferation

AKT/PKB

Growth, cell survivalH2O2

Ca 2+ intracelular

H2O2

Transcription

0%

5%

10%

15%

20%

25%

30%Colloid nodules

Follicular adenomas

Papilary carcinomas

Follicular carcinomas

H1-RAS(12/13)

H2-RAS(61)

K1-RAS(12/13)

K2-RAS(61)

N1-RAS(12/13)

N2-RAS(61)

V. Vasko et al. JCEM. 88(6):2745-2752. 2003

RAS Mutations in Thyroid Tumors

TTF-1

PAX-8

Tg

Normal Human Thyrocites

H-RAS (V-12)CONTROL4 Days 3 Weeks 3 Weeks

V Gire, D Wynford-Thomas. Oncogene. 19:737-744.2000

RAS

MAPKPI3K RalGEF

CELL SURVIVALPROLIFERATION

GROWTH

t(2;3)(q13;p25) & -20

AR Marques et al. JCEM. 87(8): 3947-3952. 2002

Chromosomalimbalance

15q loss

t(2;3)(q13;p25)

TG Kroll et al. Science. 289:1357-1360. 2000Placzkowski KA et al. PPAR Research. 2008

PAX8-PPARG

PPAR 1(exon 1)

A PAX8(exon 8)

PPAR 1(exon 1)

B PAX8(exon 10)

PAX8(exon 10)

PAX8(exon 8)

Chernobyl Disaster(April 26 1986)

66 XXX

From T Dettori et al. Genes, Chromosomes & Cancer. 38: 22-31. 2003.

Aneuploidy (33% Goiters)

M Iliszko et al. Cancer Genetic and Cytogenetcis. 161: 178-180. 2005

Cowden Syndrome

PI3K

I Vivanco, CL Sawyers. Nature Reviews. 2: 489-501.2002

PI3K/AKT Pathway(cell proliferation and survival)

PIK3CA

PTEN=Phosphatase and Tensin

Homolog

Wang Y et al. JCEM. 92:2387-2390. 2007

RAS +

PI3K/Akt +FollicularAdenoma

TSHR +/GNAS +

Follicular Carcinoma

PAX8-PPARG +

PI3K/Akt +++

PAX8-PPARG +

Hurthle Cell Adenoma

Hurthle Cell Carcinoma

GRIM-19 +(gene associated with retinoid-interferon-induced mortality-19)

mtDNA CD +(mtDNA common deletion)

PAX8-PPARG +

Santiago de Compostela Cathedral