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![Page 1: Goiter: Pathophysiology and clinical aspects Joaquín Lado Abeal, MD, PhD Department of Internal Medicine TTUHSC-SOM, Lubbock.](https://reader035.fdocuments.net/reader035/viewer/2022062302/5a4d1ad57f8b9ab059972cfb/html5/thumbnails/1.jpg)
Goiter: Pathophysiology
and clinical aspects
Joaquín Lado Abeal, MD, PhD
Department of Internal Medicine
TTUHSC-SOM, Lubbock
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Iodine intake(goitrogens)
Gender
Genetic
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From Iodine Satus Worldwide. WHO Global Data Base on Iodine Deficiency. 2004
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From Iodine Satus Worldwide. WHO Global Data Base on Iodine Deficiency. 2004
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San Bartolomeu da Mota (A Mota, Arzua, Galicia)
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Dr Gregorio Maranon
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CRETINISM
Neurological Myxedematose
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T3T4
TSH
Hyperthyrodism
High T4/T3Low TSH
Hypothyrodism
Low T4/T3High TSH
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Thyroid Hormone Synthesis
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TSH
Diferentiation Proliferation
Insulin/IGF-I
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Pituitary TSHoma
TSH
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Graves-Basedow disease
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TSHR mutations
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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
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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.
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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
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Pendred Sydrome
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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
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T4
rT3
T3
T4
D1, D2
D3
T4
T3
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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
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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
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p.R277X /c.6205+1delG WT /c.6205+1delG
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Thyroglobulin mutations
Goiter
defective hormone synthesis
high serum TSH
unfolded protein response
apoptosis
p53, NF-kB, MPAKs, VEGF
Cancer
BRAF mutations
oxidative stress
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Afrikaner cow
1 48
9TG
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INACTIVE
GDP
ACTIVE
GTP
GEF
GTPGDPGAP
Pi
RAS
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R Wetzker, Frank-D Bohmer. Transactivation joins multiple tracks to the ERK/MAPK Cascade. Nature Reviews. Molecular Biology. 4: 651-657. 2003.
PLCDAG
PKC
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RAS GTP
RalGDS Raf PLC PI3K
Ral
ProliferationCell survival
MEK
ERK
Proliferation
AKT/PKB
Growth, cell survivalH2O2
Ca 2+ intracelular
H2O2
Transcription
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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
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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
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RAS
MAPKPI3K RalGEF
CELL SURVIVALPROLIFERATION
GROWTH
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t(2;3)(q13;p25) & -20
AR Marques et al. JCEM. 87(8): 3947-3952. 2002
Chromosomalimbalance
15q loss
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t(2;3)(q13;p25)
TG Kroll et al. Science. 289:1357-1360. 2000Placzkowski KA et al. PPAR Research. 2008
PAX8-PPARG
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PPAR 1(exon 1)
A PAX8(exon 8)
PPAR 1(exon 1)
B PAX8(exon 10)
PAX8(exon 10)
PAX8(exon 8)
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Chernobyl Disaster(April 26 1986)
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66 XXX
From T Dettori et al. Genes, Chromosomes & Cancer. 38: 22-31. 2003.
Aneuploidy (33% Goiters)
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M Iliszko et al. Cancer Genetic and Cytogenetcis. 161: 178-180. 2005
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Cowden Syndrome
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PI3K
I Vivanco, CL Sawyers. Nature Reviews. 2: 489-501.2002
PI3K/AKT Pathway(cell proliferation and survival)
PIK3CA
PTEN=Phosphatase and Tensin
Homolog
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Wang Y et al. JCEM. 92:2387-2390. 2007
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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 +
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Santiago de Compostela Cathedral