Goiter Pathophysiology and clinical aspects Joaqun Lado Abeal

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

Iodine intake (goitrogens) Gender Genetic

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

TSH Hyperthyrodism Hypothyrodism T 4 High T 4/T 3 Low TSH T 3 Low T 4/T 3 High TSH

Thyroid Hormone Synthesis

TSH Diferentiation Proliferation Insulin/IGF-I

Pituitary TSHoma TSH

Graves-Basedow disease

TSHR mutations

0 100 200 300 400 500 36 35 34 33 51 49 47 45 32 31 30 November 2001 250 TT 4 (µg/dl) 1 0. 5 0. 1 15 200 150 10 100 5 50 0 0. 05 L-T 3 dose µg c. 2. d. Weight (Kg) 37 2 TSH (m. U/L) 600 0 100 250 200 150 0 TG (µg/L) Neck diameter (cm) Syndrome of Resistance to Thyroid Hormone Action (SRTH) 200 300 400 500 600 Number of days May 2003

TSH (µU/ml) 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 MA Pisarev, RD Utiger, JP Salvaneschi, N Altschuler, LJ De. Groot. Serum TSH and thyroxine in Goitrous Subjects in Argentina. J Clin Endocr. 30: 680 -681. 1970.

MULTINODULAR GOITER 28. 1. 04 11. 4. 05 30. 8. 05 NORMAL TSH µU/ml 0. 42 0. 10 0. 08 0. 35 -5. 50 FT 4 ng/dl 1. 08 0. 80 0. 85 -1. 86 FT 3 pg/ml 3. 29 3. 89 3. 65 2. 20 -4. 70 Ab TPO < 33 Ab. TG < 100

Pendred Sydrome

50 µg/day T 4 (starting March 04) Total Thyroidectomy (February 05) 100 µg/day T 4 (starting Nov 04) 100 µg/day T 4 Post surgery (starting February 05)

D 3 T 4 MCT 8 r. T 3 T 4 D 1, D 2 T 3 T 4

THYROGLOBULIN GENE MUTATIONS Red=goiter c. 6205+1 del. G R 277 X WT/ WT/ WT WT/ p. R 277 X / c. 6205+1 del. G p. R 277 X c. 6205+1 del. G T T GTAAGTTCATTG Exon 35 Exon 7 c. 886 C>T p. R 277 X wildtype mutant Intron 35 c. 6205+1 del. G Exon 35 skipping p. R 277 X / c. 6205+1 del. G

Exon 35 skipping TT GCT CAA AAT GCT CCC AGT TTT TGC CCT TTG 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 K Exon 34 P M S L Exon 36

p. R 277 X /c. 6205+1 del. G WT /c. 6205+1 del. G

Thyroglobulin mutations unfolded protein response apoptosis defective hormone synthesis p 53, NF-k. B, MPAKs, VEGF high serum TSH Goiter oxidative stress BRAF mutations Cancer

Afrikaner cow 9 TG 1 48

RAS Pi INACTIVE GEF GDP GAP GDP ACTIVE GTP

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

RAS Ral. GDS GTP Raf PLC MEK Ca 2+ intracelular PI 3 K AKT/PKB Ral ERK Proliferation Cell survival Proliferation H 2 O 2 Transcription Growth, cell survival H 2 O 2

RAS Mutations in Thyroid Tumors 30% Colloid nodules 25% Follicular adenomas Papilary carcinomas 20% Follicular carcinomas 15% 10% 5% 0% H 1 -RAS (12/13) H 2 -RAS (61) K 1 -RAS (12/13) K 2 -RAS (61) N 1 -RAS (12/13) N 2 -RAS (61) V. Vasko et al. JCEM. 88(6): 2745 -2752. 2003

Normal Human Thyrocites TTF-1 PAX-8 Tg 4 Days 3 Weeks CONTROL 3 Weeks H-RAS (V-12) V Gire, D Wynford-Thomas. Oncogene. 19: 737 -744. 2000

RAS Ral. GEF PI 3 K MAPK CELL SURVIVAL PROLIFERATION GROWTH

Chromosomal imbalance t(2; 3)(q 13; p 25) & -20 15 q loss AR Marques et al. JCEM. 87(8): 3947 -3952. 2002

PAX 8 -PPARG t(2; 3)(q 13; p 25) TG Kroll et al. Science. 289: 1357 -1360. 2000 Placzkowski KA et al. PPAR Research. 2008

A B PPARg 1 PAX 8 (exon 1) (exon 8) PPARg 1 PAX 8 (exon 1) (exon 10) (exon 8)

Chernobyl Disaster (April 26 1986)

Aneuploidy (33% Goiters) 66 XXX From T Dettori et al. Genes, Chromosomes & Cancer. 38: 22 -31. 2003.

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

Cowden Syndrome

PI 3 K/AKT Pathway (cell proliferation and survival) PIK 3 CA PI 3 K PTEN=Phosphatase and Tensin Homolog I Vivanco, CL Sawyers. Nature Reviews. 2: 489 -501. 2002

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

PAX 8 -PPARG + TSHR +/GNAS + RAS + PI 3 K/Akt + PAX 8 -PPARG + Follicular Adenoma PAX 8 -PPARG + mt. DNA CD + (mt. DNA common deletion) GRIM-19 + (gene associated with retinoidinterferon-induced mortality-19) Hurthle Cell Adenoma Hurthle Cell Carcinoma PI 3 K/Akt +++ Follicular Carcinoma

Santiago de Compostela Cathedral