Transcript Thyroid Metabolism

Biochemistry II, Barry University
March 31, 2005
A Look at Thyroid Endocrinology
Kenneth L. Campbell
Professor of Biology
University of Massachusetts at Boston
This presentation is made possible
by a grant entitled
“Shortcourses in Endocrinology at
Minority Undergraduate Institutions”
from the
National Institute of General Medical
Sciences (NIGMS)
to
The Minority Affairs Committee of
the Endocrine Society
Thyroid Functions
 Supports growth & development, especially
in the embryo & brain
 Helps regulate internal thermostasis,
particularly in the young
 Helps maintain metabolic energy balance;
increases number & size of mitochondria,
increases enzymes in the electron transport
chain, increases Na+/K+ ATPase activity
 Generally excitatory for normal cellular
functions including heart muscle
Thyroid Health Problems
Hypothyroidism (4.1F, 0.6M/1000/y)
Iodine deficiency disorders (~2x108 cases, 109 at risk;
most common thyroid & endocrine illnesses)
endemic goiter
endemic cretinism
Hashimoto’s thyroiditis (3.5F, 0.8M/1000/y)
Hyperthyroidism (0.8F,<0.1M/1000/y)
Grave’s disease (autoimmune thyrotoxicosis) (0.8F,
0.1M/1000/y, ≥ prevalence of diabetes mellitus)
Thyrotoxicosis of pregnancy (5-10% postpartun)
Toxic multinodular goiter
Thyroid neoplasia (most common endocrine neoplasms)
Benign enlargement
Malignancies
Thyroid
Anatomy
Thyroid Axis
http://www.addison.ac.uk/endocrine_modules/module1/lecturers_
material/html_files/END1.08/index.htm
Thyroid Hormone Transport
T3-TBG
R
T3- Alb
T3
T4- TTR
T3- TTR
T4
T4- Alb
T4-TBG
Thyroid Hormone Transport Proteins
T4
Plasma cap.
MW
uM
ug
kD
T4/dL
Ka T4
L/M
Ka T3
L/M
Usual
%
%
% Turnover
TT4 TT3
Occ. Rate %/d
Bd Bd
by T4
TBG
54
0.27
21
1x1010
5x108
31
13
68
80
TTR
54
4.6
350
7x107
1.4x107
2
59
11
9
Alb
66
640
50K
7x105
1x105
<0.1
5
20
11
Free
0.02 0.3
After Larsen et al., Thyroid physiology and diagnostic evaluation of
patients with thyroid disorders, Ch. 10, Larsen, Kronenberg, Melmed,
Polonsky (eds) Williams Textbook of Endocrinology, 10th ed., W.B.
Saunders Co.: Philadelphia, PA, 2003, 338, Table 10-3.
Deaminate
T4G
Thyroxine (T4)
T 4S
Deiodinase 2 & 1 (- 5’ I)
(Liver)
T3S
D1
Deiodinase 3 & 1 (- 5 I)
40%
TRIAC
T3
D3, D1 (- 5 I)
40%
3,5,3’
rT3
3,5’,3’
D1, D2 (- 5’ I)
T2
T2S
Thyroxine
Catabolism
Decarboxylate
Substrate Km
T4
T1
Thyronine
T3
rT3
D 1 - 5’ & 5 10-6
10-3
D 2 - 5’ only 10-9
10-9
D 3 - 5 only 10-9
10-9
Direct Links to Other Endocrine Axes
TRH & Somatostatin also help control PRL & GH
Indirect Links to Other Systems
Glucocorticoid
Excess  ↓ TSH, TBG, TTR, T3, T4, ↑rT3
Deficiency  ↑ TSH
Estrogens
 TBG sialylation & serum t1/2
 T4 requirement in hypothyroidism
↑ TSH in postmenopausal women
Androgens
 TBG
↓ T4 turnover in women
 T4 requirement in hypothyroidism
Mechanism of T3
4 functional intranuclear T3 receptors: α1, β1,2,3; & 1
nonfunctional receptor, α2. Expression varies with
tissue & developmental stage.
http://www.addison.ac.uk/endocrine_modules/module1/lecturers_
material/html_files/END1.08/index.htm
Pregnancy & the Thyroid Axis
Pregnancy Causes:
 TBG
Maternal Thyroid
Axis Impacts:
 Plasma volume
 T4 production
 hCG
 Total [ T4 ] & [ T3 ]
D3 expression in placenta
 T4 & T3 pool
 Renal clearance
 cardiac output
fetal T4 synthesis in 2nd &
3rd trimester
 Free T4
 O2 consumption by
fetus, placenta, uterus &
mother
 I2 requirements
 Basal TSH
 BMR
A population study of the
thyroid axis arose during
examination of the
physiological determinants
of fertility level in a nonWesternized population.
Where were
the Gainj?
The Gainj are a natural fertility
population with a low total fertility rate &
an intriguing reproductive history.
Physiology & demography were synergistic in
explaining fertility.
Female PRL made
us question impacts
on thyroid function.
But no
goiter?
Prolonged intensive nursing
keeps prolactin high &
ovulation suppressed.
[PRL] decreased during lactation, but
was still clinically high implying TRH
might be high, TSH should be high, &
T4 should be high unless iodine
deficiency was present. Thyroid axis
pathology might help explain low
fertility. Was there evidence for any?
Classic Highlands
goiter, a clear
sign of endemic
iodine-deficiency
hypothyroidism,
was absent.
http://www.j3s.net/phot
olog/ghana/
t.20030909_goiter.jpg
There were, however, at least two
cretins in the Gainj community.
Thyroid Axis Parameters
Men
Women
Hormone levels looked pretty normal
(euthyroid).
What about carrier protein levels,
albumin, prealbumin (= transthyretin),
or TBG?
Gainj men & women
have high thyroidbinding globulin but
normal thyroxine.
Compensation for
low dietary protein
& I- elevates TBG
when other carrier
proteins decline,
prolongs thryoxine
life, & decreases Ineeds.
Given the protein levels, how does T4/T3
distribute across TBG,TTR, & Alb?
While Alb & TTR are low, particularly in
women, high TBG levels might also
indicate a low-binding genetic variant.
Biochemical characteristics of Gainj
TBG & DNA sequencing of several
samples by Refetoff et al. in Chicago
implies Gainj TBG is a wild – type.
The data imply the Gainj are euthyroid
with high TBG compensating for low
Alb & TTR, probably prolonging T4
circulation time, decreasing clearance
& decreasing the iodine requirement.
Unmet elevated demands during
pregnancy & lactation may result in
fetal hypothyroidism & cretinism, in
more marginal thyroid status for
women, & in overall depression of
population fertility.
Summary:
There is an important interplay of
environmental & dietary controls
on the thyroid axis & its functions
as well as impact of sex steroids.
Exploring this network requires
evaluation of all the hormones &
binding proteins involved.
Conclusions:
Work on the Gainj has implications
for public health control of endemic
iodine deficiency: to avoid
hyperthyroid rebound while
supplementing dietary iodine, you
must also supplement protein intake
to allow binding globulins to readjust.
Acknowledgements
Support from: NSF, Umass/Boston, Sandia National Labs,
Hybritech, Quidel, Monoclonal Antibodies Inc.
Gainj Project
Turkana Project
The Gainj People
Rees Midgley
Al Hermalin
Lora Myers
Jim Wood
Pat Johnson
Ila Maslar
Diana Lai
Sam Refetoff
Peter Smouse
Peter Heywood
Michael Alpers
Brian Davison
Yan Ren
Lynne Shinto
Diane Drinkwater
Darryl Holman
Bettina Shell
All Turkana Subjects
Mike Little
Paul Leslie
Ben Campbell
Dhanesh Dookhran
Kathy Whiteman
Alexandra Evindar
William Lukas
Sandra Gray
Jeanine Quigley
Christine Sekadde
-Kigondu
Leah Kirumbi
(*in the lab at UMB)
Related Studies
Kathy O’Connor
Coralie Munro
Susannah Barsom
Ellie Brindle
Cheryl Stroud
Kai Orton
Jodiann Thompson
Yefim Proshchitskiy
Yelena Filipova
Matt Lopresti
Oliver Schultheiss
Cheryl Frederick
Steve Monfort
Malcolm Potts
David McClelland (dec)