Transcript 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
TSH
Hyperthyrodism
Hypothyrodism
T4
High T4/T3
Low TSH
T3
Low T4/T3
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
Weight (Kg)
37
2
November 2001
250
1
TT4 (µg/dl)
TSH (mU/L)
600
0.5
0.1
15
200
150
10
100
5
50
0
0.05
L-T3 dose
µg c.2.d.
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 DeGroot. 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
FT4 ng/dl
1.08
0.88
0.80
0.85-1.86
FT3 pg/ml
3.29
3.89
3.65
2.20-4.70
Ab TPO
< 33
AbTG
< 100
Pendred Sydrome
50 µg/day T4
(starting March 04)
Total Thyroidectomy
(February 05)
100 µg/day T4
(starting Nov 04)
27.11.03
28.05.04
2.02.05
100 µg/day T4
Post surgery
(starting February 05)
4.03.05
Rango
Normal
TSH, µUI/ml
3.29
1.99
0.12
6.39
0.35-5.50
FT4, ng/dl
0.51
0.77
0.91
1.25
0.85-1.86
FT3, pg/ml
3.78
3.36
2.20-4.70
Tg
1312
Anti-TPO Ab
<10
<35
Anti-TG Ab
<20
<40
IGF-1, ng/ml
Yoduria µg/L
153
100
81-267
102
25-450
D3
T4
rT3
T3
T4
D1, D2
T3
T4
THYROGLOBULIN GENE MUTATIONS
Red=goiter
c.6205+1delG
R277X
WT/
WT/
WT/
WT / WT
WT/
p.R277X /
p.R277X /
p.R277X /
c.6205+1delG
c.6205+1delG c.6205+1delG c.6205+1delG p.R277X c.6205+1delG c.6205+1delG
T
T
GTAAGTTCATTG wildtype
TAAGTTCATTG mutant
Exon 35
Exon 7
c.886C>T
p.R277X
Intron 35
c.6205+1delG
Exon 35 skipping
p.R277X /
c.6205+1delG
Exon 35 skipping
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
K
Exon 34
P M S L
Exon 36
p.R277X /c.6205+1delG
WT /c.6205+1delG
Thyroglobulin mutations
unfolded protein response
apoptosis
defective hormone synthesis
p53, NF-kB, 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
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
RalGDS
GTP
Raf
PLC
MEK
Ca 2+ intracelular
PI3K
AKT/PKB
Ral
ERK
Proliferation
Cell survival
Proliferation
H2O2
Transcription
Growth, cell survival
H2O2
RAS Mutations in Thyroid Tumors
30%
Colloid nodules
25%
Follicular adenomas
Papilary carcinomas
20%
Follicular carcinomas
15%
10%
5%
0%
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
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
RalGEF
PI3K
MAPK
CELL SURVIVAL
PROLIFERATION
GROWTH
Chromosomal
imbalance
t(2;3)(q13;p25) & -20
15q loss
AR Marques et al. JCEM. 87(8): 3947-3952. 2002
PAX8-PPARG
t(2;3)(q13;p25)
TG Kroll et al. Science. 289:1357-1360. 2000
Placzkowski KA et al. PPAR Research. 2008
A
B
PPARg 1
PAX8
(exon 1)
(exon 8)
PPARg 1
PAX8
PAX8
PAX8
(exon 1)
(exon 10)
(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
PI3K/AKT Pathway
(cell proliferation and survival)
PIK3CA
PI3K
PTEN=Phosphatase
and Tensin Homolog
I Vivanco, CL Sawyers. Nature Reviews. 2: 489-501.2002
Wang Y et al. JCEM. 92:2387-2390. 2007
PAX8-PPARG +
TSHR +/GNAS +
RAS +
PI3K/Akt +
PAX8-PPARG +
Follicular
Adenoma
PAX8-PPARG +
mtDNA CD +
(mtDNA common deletion)
GRIM-19 +
(gene associated with retinoidinterferon-induced mortality-19)
Hurthle Cell
Adenoma
Hurthle Cell
Carcinoma
PI3K/Akt +++
Follicular
Carcinoma
Santiago de Compostela Cathedral