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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