Texas A&M University, Corpus ChristiTexas A&M University, Corpus Christi

April 13, 2004April 13, 2004

A Look at Thyroid EndocrinologyA Look at Thyroid Endocrinology

Kenneth L. CampbellKenneth L. CampbellProfessor of Biology

University of Massachusetts at Boston

This presentation is made possible This presentation is made possible

by a grant entitledby a grant entitled

“Shortcourses in Endocrinology at “Shortcourses in Endocrinology at

Minority Undergraduate Institutions”Minority Undergraduate Institutions”

from the from the

National Institute of General Medical National Institute of General Medical

Sciences (NIGMS)Sciences (NIGMS)

to to

The Minority Affairs Committee of the

Endocrine Society

Thyroid Functions

Supports growth & development, especially Supports growth & development, especially in the embryo & brainin the embryo & brain

Helps regulate internal thermostasis, Helps regulate internal thermostasis, particularly in the youngparticularly in the young

Helps maintain metabolic energy balance; Helps maintain metabolic energy balance; increases number & size of mitochondria, increases number & size of mitochondria, increases enzymes in the electron transport increases enzymes in the electron transport chain, increases Nachain, increases Na++/K/K++ ATPase activity ATPase activity

Generally excitatory for normal cellular Generally excitatory for normal cellular functions including heart musclefunctions including heart muscle

Thyroid Health ProblemsThyroid Health Problems

HypothyroidismHypothyroidism (4.1F, 0.6M/1000/y)(4.1F, 0.6M/1000/y)

Iodine deficiency disorders Iodine deficiency disorders (~2x10(~2x108 8 cases, 10cases, 1099 at risk; at risk; most common thyroid & endocrine illnesses)most common thyroid & endocrine illnesses)

endemic goiterendemic goiterendemic cretinismendemic cretinism

Hashimoto’s thyroiditis Hashimoto’s thyroiditis (3.5F, 0.8M/1000/y)(3.5F, 0.8M/1000/y)

HyperthyroidismHyperthyroidism (0.8F,<0.1M/1000/y)(0.8F,<0.1M/1000/y)

Grave’s disease (autoimmune thyrotoxicosis) Grave’s disease (autoimmune thyrotoxicosis) (0.8F, (0.8F, 0.1M/1000/y, 0.1M/1000/y, ≥ prevalence of diabetes mellitus)≥ prevalence of diabetes mellitus)Thyrotoxicosis of pregnancy Thyrotoxicosis of pregnancy (5-10% postpartun)(5-10% postpartun)Toxic multinodular goiterToxic multinodular goiter

Thyroid neoplasiaThyroid neoplasia (most common endocrine neoplasms)(most common endocrine neoplasms)

Benign enlargementBenign enlargement

MalignanciesMalignancies

Thyroid Thyroid AnatomyAnatomy

Thyroid AxisThyroid Axis

http://www.addison.ac.uk/endocrine_modules/module1/lecturers_material/html_files/END1.08/index.htm

T4

T4- Alb

T4- TTR T3

T4-TBG

T3-TBG

T3- TTR

T3- Alb

R

Thyroid Hormone TransportThyroid Hormone Transport

Thyroid Hormone Transport ProteinsThyroid Hormone Transport Proteins

MW kD

Plasma uM

T4 cap. ug

T4/dL

Ka T4 L/M

Ka T3 L/M

Usual %

Occ. by T4

Turnover Rate %/d

% TT4 Bd

% TT3 Bd

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.

Substrate Km

T4 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

Thyroxine (TThyroxine (T44))

TT33 rTrT33

TT33SS

TRIACTRIAC

TT22

TT11

ThyronineThyronine

Deiodinase 2 & 1 (- 5’ I)

3,5,3’ 3,5’,3’

Deiodinase 3 & 1 (- 5 I)40% 40%

D1, D2 (- 5’ I)D3, D1 (- 5 I)

TT22SS

D1

(Liver)

Deaminate

TT44SS

TT44GG

Decarboxylate

Thyroxine Thyroxine CatabolismCatabolism

Direct Links to Other Endocrine AxesDirect Links to Other Endocrine AxesTRH & Somatostatin also help control PRL & GH

Indirect Links to Other SystemsIndirect Links to Other SystemsGlucocorticoid

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 TMechanism of T33

4 functional intranuclear T4 functional intranuclear T33 receptors: receptors: 1, 1, ββ1,2,3; & 1 1,2,3; & 1

nonfunctional receptor, nonfunctional receptor, αα2. Expression varies with 2. Expression varies with tissue & developmental stage.tissue & developmental stage.

http://www.addison.ac.uk/endocrine_modules/module1/lecturers_material/html_files/END1.08/index.htm

Pregnancy & the Thyroid AxisPregnancy & the Thyroid Axis

Pregnancy Causes:Pregnancy Causes:

TBGTBG

Plasma volumePlasma volume

hCGhCG

D3 expression in placentaD3 expression in placenta

Renal clearanceRenal clearance

fetal Tfetal T44 synthesis in 2 synthesis in 2ndnd & & 33rdrd trimester trimester

OO22 consumption by fetus, consumption by fetus, placenta, uterus & motherplacenta, uterus & mother

Maternal Thyroid Maternal Thyroid Axis Impacts:Axis Impacts:

TT44 production production

Total [ TTotal [ T4 4 ] & [ T] & [ T3 3 ]]

TT44 & T & T33 pool pool

cardiac outputcardiac output

Free TFree T44

Basal TSHBasal TSH

II22 requirements requirements

BMRBMR

A population study of the A population study of the thyroid axis arose during thyroid axis arose during examination of the examination of the physiological determinants physiological determinants of fertility level in a non-of fertility level in a non-Westernized population.Westernized population.

Where were Where were the Gainj?the Gainj?

The Gainj are a natural fertility The Gainj are a natural fertility population with a low total fertility rate & population with a low total fertility rate &

an intriguing reproductive history.an intriguing reproductive history.

Physiology & demography were synergistic in Physiology & demography were synergistic in explaining fertility.explaining fertility.

Female PRL made Female PRL made us question impacts us question impacts on thyroid function.on thyroid function.

But no But no goiter?goiter?

Prolonged intensive nursing Prolonged intensive nursing keeps prolactin high & keeps prolactin high & ovulation suppressed.ovulation suppressed.

[PRL] decreased during lactation, but [PRL] decreased during lactation, but was still clinically high implying TRH was still clinically high implying TRH might be high, TSH should be high, & might be high, TSH should be high, & TT44 should be high unless iodine should be high unless iodine

deficiency was present. Thyroid axis deficiency was present. Thyroid axis pathology might help explain low pathology might help explain low fertility. Was there evidence for any?fertility. Was there evidence for any?

http://www.j3s.net/photolog/ghana/

t.20030909_goiter.jpg

Classic Highlands Classic Highlands goiter, a clear goiter, a clear sign of endemic sign of endemic iodine - deficiency iodine - deficiency hypothyroidism, hypothyroidism, was absent.was absent.

There were, however, at least two There were, however, at least two cretins in the Gainj community.cretins in the Gainj community.

Thyroid Axis ParametersThyroid Axis Parameters

Hormone levels looked pretty normal Hormone levels looked pretty normal (euthyroid). (euthyroid).

What about carrier protein levels, What about carrier protein levels, albumin, prealbumin (= transthyretin), albumin, prealbumin (= transthyretin), or TBG?or TBG?

Men Women

Gainj men & women Gainj men & women have high thyroid-have high thyroid-

binding globulin but binding globulin but normal thyroxine. normal thyroxine. Compensation for Compensation for low dietary proteinlow dietary protein

& I& I-- elevates TBG elevates TBG when other carrier when other carrier proteins decline, proteins decline,

prolongs thryoxine prolongs thryoxine life, & decreases Ilife, & decreases I- -

needs.needs.

Given the protein levels, how does TGiven the protein levels, how does T44/T/T33

distribute across TBG,TTR, & Alb?distribute across TBG,TTR, & Alb?

While Alb & TTR are low, particularly in While Alb & TTR are low, particularly in women, high TBG levels might also women, high TBG levels might also indicate a low-binding genetic variant.indicate a low-binding genetic variant.

Biochemical characteristics of Gainj Biochemical characteristics of Gainj TBG & DNA sequencing of several TBG & DNA sequencing of several samples by Refetoff samples by Refetoff et al.et al. in Chicago in Chicago implies Gainj TBG is a wild – type.implies Gainj TBG is a wild – type.

The data imply the Gainj are The data imply the Gainj are euthyroideuthyroid with with high TBG compensating for low high TBG compensating for low Alb & TTRAlb & TTR, probably prolonging T, probably prolonging T44 circulation time, decreasing clearance circulation time, decreasing clearance & decreasing the iodine requirement. & decreasing the iodine requirement. Unmet elevated demands during Unmet elevated demands during pregnancy & lactation may result in pregnancy & lactation may result in fetal hypothyroidism & cretinism, in fetal hypothyroidism & cretinism, in more marginal thyroid status for more marginal thyroid status for women, & in overall depression of women, & in overall depression of population fertility. population fertility.

There is an important interplay of There is an important interplay of environmental & dietary controls environmental & dietary controls on the thyroid axis & its functions on the thyroid axis & its functions as well as impact of sex steroids. as well as impact of sex steroids. Exploring this network requires Exploring this network requires evaluation of all the hormones & evaluation of all the hormones & binding proteins involved.binding proteins involved.

Summary:Summary:

Work on the Gainj has implications Work on the Gainj has implications for public health control of endemic for public health control of endemic iodine deficiency: to avoid iodine deficiency: to avoid hyperthyroid rebound while hyperthyroid rebound while supplementing dietary iodine, you supplementing dietary iodine, you must also supplement protein intake must also supplement protein intake to allow binding globulins to readjust.to allow binding globulins to readjust.

Conclusions:Conclusions:

Support from: NSF, Umass/Boston, Sandia National Labs, Support from: NSF, Umass/Boston, Sandia National Labs, Hybritech, Quidel, Monoclonal Antibodies Inc.Hybritech, Quidel, Monoclonal Antibodies Inc.

AcknowledgementsAcknowledgements

Gainj ProjectGainj ProjectThe Gainj PeopleThe Gainj PeopleRees MidgleyRees MidgleyAl HermalinAl HermalinLora MyersLora MyersJim WoodJim WoodPat JohnsonPat JohnsonIla Maslar Ila Maslar Diana LaiDiana LaiSam Refetoff Sam Refetoff Peter SmousePeter SmousePeter HeywoodPeter HeywoodMichael AlpersMichael AlpersBrian DavisonBrian DavisonYan Ren Yan Ren Lynne ShintoLynne ShintoDiane DrinkwaterDiane DrinkwaterDarryl HolmanDarryl HolmanBettina ShellBettina Shell

Related StudiesRelated StudiesKathy O’ConnorKathy O’ConnorCoralie MunroCoralie MunroSusannah Barsom Susannah Barsom Ellie Brindle Ellie Brindle Cheryl StroudCheryl StroudKai OrtonKai OrtonJodiann ThompsonJodiann ThompsonYefim ProshchitskiyYefim ProshchitskiyYelena FilipovaYelena FilipovaMatt LoprestiMatt LoprestiOliver SchultheissOliver SchultheissCheryl FrederickCheryl FrederickSteve MonfortSteve MonfortMalcolm PottsMalcolm PottsDavid McClelland (dec)David McClelland (dec)

Turkana ProjectTurkana ProjectAll Turkana SubjectsAll Turkana SubjectsMike LittleMike LittlePaul LesliePaul LeslieBen CampbellBen CampbellDhanesh DookhranDhanesh DookhranKathy WhitemanKathy WhitemanAlexandra EvindarAlexandra EvindarWilliam LukasWilliam LukasSandra GraySandra GrayJeanine QuigleyJeanine QuigleyChristine SekaddeChristine Sekadde -Kigondu-KigonduLeah KirumbiLeah Kirumbi

(*in the lab at UMB)(*in the lab at UMB)