Goiter: Pathophysiology and clinical aspects

1
Goiter Pathophysiology and clinical aspects
Joaquín Lado Abeal, MD, PhD
Department of Internal Medicine TTUHSC-SOM,
Lubbock
2
Iodine intake (goitrogens)
Gender
Genetic
3
From Iodine Satus Worldwide. WHO Global Data Base
on Iodine Deficiency. 2004
4
From Iodine Satus Worldwide. WHO Global Data Base
on Iodine Deficiency. 2004
5
(No Transcript)
6
(No Transcript)
7
Dr Gregorio Maranon
8
CRETINISM
Myxedematose
Neurological
9
(No Transcript)
10
(No Transcript)
11
(No Transcript)
12
(No Transcript)
13
(No Transcript)
14
Thyroid Hormone Synthesis
15
TSH
Diferentiation
Proliferation
16
Pituitary TSHoma
TSH
17
Graves-Basedow disease
18
(No Transcript)
19
Syndrome of Resistance to Thyroid Hormone Action
(SRTH)
37
36
Neck diameter (cm)
35
34
Weight (Kg)
33
32
31
30
November 2001
2
1
0.5
TSH (mU/L)
(µg/L)
TT4 (µg/dl)
TG
0.1
0.
05
L-T
dose
3
µg c.2.d.
Number of days
May 2003
20
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 lt0.01 ?
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 lt0.05 NS
Goiter, grado I II 7 2.4-4.8 4 ? 0.8 lt0.05 NS
Goiter, grado III 5 2.8-7.2 4 ? 0.8 lt0.05 NS
MA Pisarev, RD Utiger, JP Salvaneschi, N
Altschuler, LJ DeGroot. Serum TSH and thyroxine
in Goitrous Subjects in Argentina. J Clin Endocr.
30680-681. 1970.
21
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
1.08
FT4 ng/dl
0.88
0.80
0.85-1.86
3.29
3.89
3.65
2.20-4.70
FT3 pg/ml
Ab TPO
lt 33
AbTG
lt 100
22
Pendred Sydrome
23
Total Thyroidectomy (February 05)
50 µg/day T4 (starting March 04)
100 µg/day T4 Post surgery (starting February 05)
100 µg/day T4 (starting Nov 04)
24
rT3
D3
T3
MCT8
T4
T4
T3
D1, D2
T4
25
THYROGLOBULIN GENE MUTATIONS
Redgoiter
R277X
c.62051delG
p.R277X / c.62051delG
WT/ p.R277X
WT/ c.62051delG
WT / WT
WT/ c.62051delG
p.R277X / c.62051delG
p.R277X / c.62051delG
p.R277X / c.62051delG
WT/ c.62051delG
T
Exon 35
Intron 35
Exon 7
26
(No Transcript)
27
(No Transcript)
28
(No Transcript)
29
p.R277X /c.62051delG
WT /c.62051delG
30
(No Transcript)
31
(No Transcript)
32
Thyroglobulin mutations
unfolded protein response
apoptosis
defective hormone synthesis
p53, NF-kB, MPAKs, VEGF
high serum TSH
Goiter
oxidative stress
BRAF mutations
Cancer
33
Afrikaner cow
9
TG
48
1
34
(No Transcript)
35
(No Transcript)
36
(No Transcript)
37
(No Transcript)
38
(No Transcript)
39
(No Transcript)
40
Normal Human Thyrocites
TTF-1
PAX-8
Tg
4 Days
3 Weeks
3 Weeks
H-RAS (V-12)
CONTROL
V Gire, D Wynford-Thomas. Oncogene.
19737-744.2000
41
(No Transcript)
42
(No Transcript)
43
PAX8-PPARG
t(23)(q13p25)
TG Kroll et al. Science. 2891357-1360.
2000 Placzkowski KA et al. PPAR Research. 2008
44
(No Transcript)
45
(No Transcript)
46
Chernobyl Disaster (April 26 1986)
47





(No Transcript)
48
(No Transcript)
49
Aneuploidy (33 Goiters)
66 XXX
From T Dettori et al. Genes, Chromosomes
Cancer. 38 22-31. 2003.
50
M Iliszko et al. Cancer Genetic and Cytogenetcis.
161 178-180. 2005
51
Cowden Syndrome
52
PI3K/AKT Pathway (cell proliferation and survival)
PIK3CA
PI3K
PTENPhosphatase and Tensin Homolog
I Vivanco, CL Sawyers. Nature Reviews. 2
489-501.2002
53
Wang Y et al. JCEM. 922387-2390. 2007
54
PAX8-PPARG
TSHR /GNAS
PAX8-PPARG
RAS
FollicularAdenoma
Follicular Carcinoma
PI3K/Akt
PI3K/Akt
PAX8-PPARG
mtDNA CD (mtDNA common deletion)
GRIM-19 (gene associated with
retinoid- interferon-induced mortality-19)
Hurthle Cell Adenoma
Hurthle Cell Carcinoma
55
Santiago de Compostela Cathedral