Comprehensive Reviewof Thyroid Embryology Anatomy Histologyand Physiologyfor Surgeons

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Comprehensive Review of Thyroid Embryology, Anatomy, Histology, and

Physiology for Surgeons
Article in International Journal of Otolaryngology and Head & Neck Surgery · July 2018
DOI: 10.4236/ijohns.2018.74019
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6 authors, including:
Rodrigo Arrangoiz Fernando Cordera

Mount Sinai Medical Center Centro Médico ABC
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Manuel Muñoz Eduardo Moreno

Centro Médico ABC University of La Serena
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International Journal of Otolaryngology and Head & Neck Surgery, 2018, 7, 160-188
http://www.scirp.org/journal/ijohns
ISSN Online: 2168-5460
ISSN Print: 2168-5452
Comprehensive Review of Thyroid Embryology,

Anatomy, Histology, and Physiology for
Surgeons
Rodrigo Arrangoiz*, Fernando Cordera, David Caba, Manuel Muñoz,

Eduardo Moreno, Enrique Luque de León
D e p a r tm e n t o f S u r g ic a l O n c o lo g y /H e a d a n d N e c k D iv is io n o f th e A m e r ic a n B r itis h C o w d r a y M e d ic a l C e n te r , M e x ic o C ity , M e x ic o
H o w to c ite th is p a p e r : A rr a n g o iz , R ., Abstract
C o rd e ra , F ., C a b a , D ., M u ñ o z , M ., M o r e n o ,
E . a n d d e L e ó n , E .L . ( 2 0 1 8 ) C o m p r e h e n s iv e E m il T h e o d o r K o c h e r a n d T h e o d o r B illr o th p io n e e r e d th e s u r g ic a l m a n a g e -
R e v ie w o f T h y r o id E m b r y o lo g y , A n a to m y , m e n t o f th y r o id d is e a s e . T h e ir s u r g ic a l te c h n iq u e s , k n o w le d g e o f th y r o id
H is to lo g y , a n d P h y s io lo g y fo r S u rg e o n s.
a n a to m y , e m b r y o lo g y , h is to lo g y , p h y s io lo g y , a n d a n tis e p s is p r a c tic e s tr a n s i-
I n te r n a tio n a l J o u r n a l o f O to la r y n g o lo g y
a n d H e a d & N e ck S u rg e ry , 7 , 1 6 0 -1 8 8 . tio n e d a life - th r e a te n in g o p e r a tio n to o n e w ith a c c e p ta b le m o r b id ity . T h e
h t t p s :/ / d o i.o r g / 1 0 .4 2 3 6 / ijo h n s .2 0 1 8 .7 4 0 1 9 m o d e r n h e a d a n d n e c k s u r g e o n s h o u ld h a v e a m e tic u lo u s s u r g ic a l te c h n iq u e ,
c o m b in e d w ith a th o r o u g h u n d e r s ta n d in g o f th y r o id e m b r y o lo g y a n d a n a to -
R e c e iv e d : M a y 2 9 , 2 0 1 8
m y th a t is c e n tr a l to th e u n d e r s ta n d in g a n d tr e a tm e n t o f th e d iffe r e n t d is e a s e
A c c e p te d : J u ly 1 3 , 2 0 1 8
P u b lis h e d : J u ly 1 6 , 2 0 1 8
p r o c e s s e s o f th e th y r o id g la n d a n d th e c o n s e q u e n c e s o f th y r o id g la n d s u r g e r y .
I n th is m a n u s c r ip t w e w ill b e e x a m in in g th y r o id g la n d e m b r y o lo g y , a n a to m y ,
C o p y r ig h t © 2 0 1 8 b y a u th o rs a n d h is to lo g y , a n d p h y s io lo g y th a t is e s s e n tia l to th e p r a c tic in g th y r o id s u r g e o n .
S c ie n tific R e se a r c h P u b lis h in g I n c .
T h is w o r k is lic e n s e d u n d e r th e C r e a tiv e
C o m m o n s A ttr ib u tio n In te r n a tio n a l
Keywords
L ic e n s e ( C C B Y 4 .0 ) . T h y r o id G la n d E m b r y o lo g y , T h y r o id G la n d A n a to m y , T h y r o id G la n d H is to lo g y ,
h t t p :/ / c r e a tiv e c o m m o n s .o r g / lic e n s e s / b y / 4 .0 /
T h y r o id G la n d P h y s io lo g y , T h y r o id G la n d
O p e n A c c e ss
1. Introduction
T h e m o d e r n h e a d a n d n e c k s u r g e o n /e n d o c r in e s u r g e o n /th y r o id s u r g e o n s h o u ld
h a v e a c o m p le te u n d e r s ta n d in g o f th e b a s ic s c ie n c e b e h in d th e d e v e lo p m e n t o f
th e th y r o id a n d p a r a th y r o id g la n d s a s w e ll a s k n o w le d g e o f th e p o s s ib le c o n g e -
n ita l a b n o r m a litie s a r is in g o u t o f th e s e g la n d s , a s th e y m a y im p a c t th e c o m -
p le te n e s s o f s u r g e r y a s w e ll a s th e c o m p lic a tio n s o f s u r g e r y . T h e m o d e r n th y r o id
s u r g e o n c o m e s to a m o r e in n a te u n d e r s ta n d in g o f s u r g ic a l a n a to m y th r o u g h th e
c o m p r e h e n s iv e g r a s p o f th e u n d e r ly in g fo r m a tiv e e m b r y o lo g y .
T h e life tim e r is k o f d e v e lo p in g th y r o id d y s fu n c tio n is c o m m o n [ 1 ] [ 2 ] . S u b -
DOI: 10.4236/ijohns.2018.74019 Jul. 16, 2018 160 Int. J. Otolaryngology and Head & Neck Surgery
R. Arrangoiz et al.
c lin ic a l a n d o v e r t h y p o th y r o id is m o c c u r s in 4 .6 % to 9 .5 % [3 ] [4 ], w h e re a s su b -
c lin ic a l a n d o v e r t h y p e r th y r o id is m o c c u r s in 1 .3 % to 2 .2 % o f th e p o p u la tio n [ 1 ]
[ 3 ] [ 4 ] . T h e in c id e n c e o f th y r o id c a n c e r h a s b e e n in c r e a s in g s te a d ily s in c e th e
m id - 1 9 9 0 s w ith a n e stim a te d in c id e n c e o f 5 3 ,9 9 0 in 2 0 1 8 [ 5 ] . T h is c a n c e r
r e p r e s e n ts th e m o s t c o m m o n e n d o c r in e m a lig n a n c y a n d a c c o u n ts fo r a p p r o x -
im a te ly 3 % o f a ll h u m a n m a lig n a n c ie s , w ith 7 5 % o f c a s e s o c c u r r in g in w o m e n
[ 5 ] [ 6 ] . A s w e c a n s e e th e p r e v a le n c e o f th y r o id d is e a s e is h ig h a n d , in m a n y in -
s ta n c e s , s u r g e r y fo r m s a n in te g r a l p a r t o f th e tr e a tm e n t, s o a c o m p le te u n d e r -
s ta n d in g o f th e e m b r y o lo g y , a n a to m y , h is to lo g y , a n d p h y s io lo g y is e s s e n tia l to
a n y s u r g e o n th a t w ill b e m a n a g in g th y r o id d is e a s e s .
2. Thyroid Gland Embryogenesis

T h e m o d e r n h e a d a n d n e c k s u r g e o n s h o u ld h a v e a c o m p le te g r a s p o f th e e m -
b r y o g e n e s is o f th e th y r o id g la n d a s w e ll a s k n o w le d g e o f th e p o s s ib le c o n g e n ita l
a n o m a lie s a r is in g o u t o f th is g la n d , a s th e y m a y in flu e n c e th e c o m p le te n e s s o f
th e s u r g e r y a s w e ll a s th e c o m p lic a tio n s a r is in g fr o m o p e r a tio n s o f th e th y r o id
g la n d .
T h e t h y r o id g la n d is t h e f ir s t o f t h e b o d y ’s e n d o c r in e g la n d s t o d e v e lo p , a p -
p e a r in g a s a n o u tp o u c h in g o f th e p r im itiv e fo r e g u t a r o u n d th e th ir d w e e k o f
g e s ta tio n ( r o u g h ly th e 2 4 th
d a y ) [ 7 ] . T h e th y r o id g la n d fo r m s a s a p r o life r a tio n
( th ic k e n in g ) o f th e e n d o d e r m a l e p ith e lia l c e lls fo u n d o n th e m e d ia n s u r fa c e o f
th e d e v e lo p in g p h a r y n g e a l flo o r [ 8 ] . T h e s ite o f th is d e v e lo p m e n t lie s b e tw e e n
tw o k e y s tr u c tu r e s , th e tu b e r c u lu m im p a r a n d th e c o p u la , a n d is r e c o g n iz e d a s
th e fo ra m e n c e c u m (F ig u r e 1 ) [9 ].
T h e fo ra m e n c e c u m lo c a te d a t th e b a s e o f th e to n g u e is th e s ite o f o r ig in o f th e
th y r o id g la n d a t th e ju n c tio n b e tw e e n th e fir s t a n d s e c o n d b r a n c h ia l ( p h a r y n -
g e a l) p o u c h e s , im m e d ia te ly d o r s a l to th e a o r tic s a c [ 8 ] [ 1 0 ] . T h e th y r o id g la n d
h a s a d o u b le e m b r y o lo g ic o r ig in : th e p r im itiv e p h a r y n x a n d th e n e u r o e c to d e r -
m a l/n e u r a l c r e s t [ 9 ] . T h e th y r o id g la n d in itia lly a r is e s c a u d a l to th e tu b e r c u lu m
F ig u r e 1 . O r ig in o f th y r o id g la n d a t th e fo r a m e n c e c u m a n d th e tu b e r c u lu m im p a r ( m e d ia n to n g u e b u d ) .
DOI: 10.4236/ijohns.2018.74019 161 Int. J. Otolaryngology and Head & Neck Surgery
R. Arrangoiz et al.
im p a r , w h ic h is a ls o k n o w n a s th e m e d ia n to n g u e b u d ( F ig u r e 1 ) [ 1 1 ] . T h is e m -
b r y o n ic s w e llin g d e v e lo p s fr o m th e fir s t b r a n c h ia l a r c h a n d o c c u r s o n th e m id -
lin e o f th e flo o r o f th e d e v e lo p in g p h a r y n x , e v e n tu a lly h e lp in g fo r m th e to n g u e
a s th e tw o la te r a l lin g u a l s w e llin g s o v e r g r o w it [ 1 1 ] . T h e fo r a m e n c e c u m b e g in s
r o s tr a l to th e c o p u la , a ls o k n o w n a s th e h y p o b r a n c h ia l ( h y p o p h a r y n g e a l) e m i-
n e n c e ( F ig u r e 1 ) . T h is m e d ia n e m b r y o lo g ic s w e llin g c o n s is ts o f m e s o d e r m th a t
a r is e s fr o m th e s e c o n d b r a n c h ia l p o u c h ( a lth o u g h th e th ir d a n d fo u r th b r a n c h ia l
p o u c h e s a r e a ls o in v o lv e d ) . T h e th y r o id g la n d , th e r e fo r e , o r ig in a te s b e tw e e n th e
fir s t a n d s e c o n d b r a n c h ia l p o u c h e s [ 1 0 ] .
T h e in itia l th y r o id p r e c u r s o r , th e th y r o id p r im o r d iu m , s ta r ts a s a s im p le m id -
lin e th ic k e n in g ( e n d o d e r m ) a n d d e v e lo p s to fo r m th e th y r o id d iv e r tic u lu m o r
th y r o id a n la g e ( th is m e d ia n a n la g e fo r m s th e b u lk o f th e th y r o id g la n d ) [ 1 2 ] .
T h is s tr u c tu r e a t th e o u ts e t is in itia lly h o llo w , th o u g h it la te r s o lid ifie s ( fo r m in g
th e fo llic u la r e le m e n ts o f th e th y r o id g la n d ) a n d b e c o m e s b ilo b e d . D iv is io n o f
th e th y r o id g la n d in to la te r a l lo b e s , if n o t p r e s e n t fr o m th e b e g in n in g , ta k e s p la c e
s o e a r ly th a t it is im p o s s ib le to e s ta b lis h w h e th e r th e th y r o id a r is e s a s a s in g le
u n it o r a s a p a ir e d o r g a n . T h e s ta lk u s u a lly h a s a lu m e n , th e th y r o g lo s s a l d u c t,
th a t d o e s n o t d e s c e n d in to th e la te r a l lo b e s [ 1 2 ] . T h e tw o lo b e s a r e lo c a te d o n
e ith e r s id e o f th e m id lin e a n d a r e c o n n e c te d v ia a n is th m u s ( F ig u r e 2 ) . T h is
th y r o id a n la g e fo llo w s th e p r im itiv e h e a r t a s it d e s c e n d s c a u d a lly [ 1 2 ] . E a r ly
d u r in g th e fifth w e e k o f g e s ta tio n , th e a tte n u a te d d u c t lo s e s its lu m e n a n d s u b -
s e q u e n tly b r e a k s in to fr a g m e n ts . T h e p r o x im a l p a r t r e tr a c ts a n d v a n is h e s , le a v -
in g o n ly th e fo r a m e n c e c u m a t th e b a s e o f th e to n g u e to m a r k its o r ig in , a n d th e
c a u d a l e n d d e v e lo p s a s th e b ilo b e d e n c a p s u la te d th y r o id g la n d a n d r e a c h e s its
fin a l a d u lt p o s itio n b y th e 7 th
w e e k o f g e sta tio n [9 ].
T h e p a ir e d la te r a l a n la g e s o r ig in a te fr o m th e v e n tr a l p o r tio n s o f th e fo u r th
a n d fifth b r a n c h ia l p o u c h e s a n d fu s e w ith th e m e d ia n th y r o id a n la g e a t a p p r o x -
im a te ly th e fifth w e e k o f g e s ta tio n [ 7 ] , c o n tr ib u tin g u p to 3 0 % o f th e th y r o id
g la n d w e ig h t [ 1 2 ] . T h e la te r a l a n la g e s a r e n e u r o e c to d e r m a l/n e u r a l c r e s t in o r ig in
( u ltim o b r a n c h ia l b o d ie s ) a n d p r o d u c e th e c a lc ito n in p r o d u c in g p a r a fo lic u lla r o r
C c e lls ( fr o m th e n e u r a l c r e s t th e s e th e C - c e lls m ig r a te to th e u ltim o b r a n c h ia l
b o d ie s ) , w h ic h c o m e to lie in th e s u p e r io r p o s te r io r r e g io n o f th e th y r o id g la n d
F ig u r e 2 . T h y r o id F o llic le s a n d th y r o id p a r a fo llic u la r o r C c e lls .
R. Arrangoiz et al.
[ 7 ] [ 8 ] [ 1 2 ] [ 1 3 ] . T h e fu s io n o f th e m e d ia n th y r o id a n la g e a n d th e u ltim o b r a n -
c h ia l b o d ie s e x p la in s w h y th e p a r a fo llic u la r c e lls o r C c e lls a r e n o t s c a tte r e d
th r o u g h o u t th e e n tir e th y r o id b u t a r e lim ite d to a r e g io n d e e p w ith in th e m id d le
to u p p e r th ir d s o f th e la te r a l lo b e s a lo n g a n im a g in a r y c e n tr a l lo b a r a x is [ 1 4 ] . T h e
b a s e s fo r th e fu s io n o f th e m e d ia n a n d la te r a l th y r o id a n la g e s is u n c le a r , b u t th e
s ite o f th e fu s io n o f th e s e tw o s tr u c tu r e s is s ta te d to o c c u r a t th e tu b e r c le o f Z u c k -
e r k a n d l [ 1 5 ] [ 1 6 ] . T h e p a r a fo lic u lla r o r C c e lls b e lo n g to a g r o u p o f n e u r a l- c r e s t
d e r iv a tiv e s k n o w n a s th e a m in e p r e c u r s o r u p ta k e a n d d e c a r b o x y la tio n c e lls
(A P U D ) [1 7 ].
T h e th y r o id fo llic u la r c e lls d e v e lo p fr o m th e m e d ia n th y r o id a n la g e a n d b e -
c o m e a p p a re n t a ro u n d th e 8 th
w e e k o f g e s ta tio n a n d s ta r t p r o d u c in g c o llo id a n d
ta k e u p r a d io a c tiv e io d in e a r o u n d th e 1 1 th
w e e k o f g e s ta tio n [ 8 ] [ 1 2 ] . E v id e n c e
o f th y r o x in e c o m e s w ith th e a p p e a r a n c e o f c o llo id [ 8 ] [ 1 2 ] . T h e d e v e lo p m e n t
o f th e th y r o id fo llic le is h e r a ld e d b y th e a p p e a r a n c e o f a n in tr a c e llu la r p e r io d ic
a c id - S c h iff ( P A S ) - p o s itiv e m a te r ia l, w h ic h le a d s to fo llic le fo r m a tio n b y b u d d in g
o r d iv is io n o f th e p r im a r y fo llic le s [ 1 2 ] . T h e h is to lo g ic d iffe r e n tia tio n o f th e
th y r o id g la n d c a n b e c o n c e p tu a liz e d in to th r e e s ta g e s : p r e - c o llo id (7 to 1 3
w e e k s ) ; c o llo id ( 1 3 to 1 4 w e e k s ) ; a n d fo llic u la r ( a fte r 1 4 w e e k s ) [ 1 2 ] .
3. Thyroid Gland Histology

T h e th y r o id g la n d is e n c lo s e d b y th e th y r o id c a p s u le , w h ic h is a th in , d e n s e la y e r
o f c o n n e c tiv e tis s u e th a t s e n d s s e p ta in to th e th y r o id p a r e n c h y m a , s u b d iv id in g
th e th y r o id g la n d in to s e v e r a l lo b u le s [ 8 ] . E a c h th y r o id lo b u le c o n ta in s 2 0 to 4 0
r o u n d to o v a l fo llic le s , m e a s u r in g 3 0 to 5 0 0 m ic r o n s in d ia m e te r [ 8 ] . E a c h th y -
r o id fo llic le is lin e d b y c u b o id a l e p ith e lia l c e lls a n d c o n ta in s a c e n tr a l s to r e o f
c o llo id s e c r e te d b y th e e p ith e lia l c e lls u n d e r th e in flu e n c e o f th e p itu ita r y h o r -
m o n e th y r o id s tim u la tin g h o r m o n e ( T S H ) [ 1 8 ] [ 1 9 ] ( F ig u r e 2 ) . T h e r e a r e a b o u t
3 × 1 0 6
fo llic le s in th e a d u lt m a le th y r o id g la n d [ 1 9 ] . T h e th y r o id fo llic le s a r e s e -
p a r a te d b y a th in c o n n e c tiv e tis s u e s tr o m a c o n ta in in g ly m p h a tic v e s s e l, b lo o d
v e s s e ls a n d n e r v e s . T h e lu m e n o f th e th y r o id fo llic le c o n ta in s c o llo id , w h ic h is
s c a llo p e d a n d p a le in fo llic le s w ith a c tiv e s e c r e to r y a c tiv ity , d e n s e ly e o s in o p h ilic
in in a c tiv e fo llic le s , a n d m o r e flo c c u le n t ( “ lik e a c lu m p o r tu ft o f w o o l” ) a n d b a -
s o p h ilic in th e e ld e r ly . T a b le 1 d e s c r ib e s th e a c tio n s o f th e th y r o id fo llic u la r
c e lls .
T a b le 1 . A c tio n s o f th e th y r o id fo llic u la r c e lls [ 9 5 ] .
S y n th e s is o f th y r o g lo b u lin
Io d in a tio n
S to r a g e o f th y r o g lo b u lin
R e s o r p tio n o f th y r o g lo b u lin
H y d r o ly s is o f th y r o g lo b u lin
R e le a s e o f th y r o id h o r m o n e in to th e b lo o d a n d ly m p h a tic s
R. Arrangoiz et al.
T h e s e c o n d g r o u p o f th y r o id s e c r e to r y c e lls is th e p a r a fo llic u la r o r C c e lls , d e -

r iv e d fr o m th e n e u r a l c r e s t, w h ic h c o n ta in a n d s e c r e te th e h o r m o n e c a lc ito n in
[ 8 ] . T h e y a r e lo c a te d a s in d iv id u a l c e lls o r c lu m p to g e th e r in s m a ll g r o u p s in th e
in te r - fo llic u la r s tr o m a ( in th e u p p e r p o le s o f th e th y r o id lo b e s ) [ 8 ] [ 1 8 ] [ 1 9 ] . T h e
p a r a fo llic u la r o r C c e lls r e p r e s e n t r o u g h ly 0 .1 % o f th e th y r o id g la n d , id e n tify in g
te n p a r a fo llic u la r c e lls p e r lo w p o w e r fie ld in a d u lts [ 2 0 ] ( F ig u r e 2 ) . T h e p a r a fo l-
lic u la r c e lls a r e m o r e a b u n d a n t in n e o n a te s , d e c r e a s e in n u m b e r a d u lts , o n ly to
in c r e a s e a n d a p p e a r a s n o d u la r a g g r e g a te s a fte r a g e 6 0 y e a r s [ 2 1 ] . T h e C c e lls
h a v e p a le to c le a r c y to p la s m , o v a l n u c le i, a n d a r e d iffic u lt to id e n tify w ith H a n d
E s ta in , s o a s ta in fo r c a lc ito n in is u s e d fo r th e ir id e n tific a tio n [ 2 1 ] .
4. Thyroid Gland Anatomy

T h e th y r o id g la n d is a n e x tr e m e ly v a s c u la r o r g a n th a t is b r o w n to r e d in c o lo r ,
fir m in c o n s is te n c y , lo c a te d p o s te r io r to th e s tr a p m u s c le s , a n d a n te r io r ly in th e
lo w e r a s p e c t o f th e n e c k , e x te n d in g fr o m th e le v e l o f th e fifth c e r v ic a l v e r te b r a
d o w n to th e fir s t th o r a c ic v e r te b r a [ 1 8 ] [ 1 9 ] . T h e s h a p e o f th e th y r o id g la n d v a -
r ie s fr o m a n H to a U s h a p e a n d is fo r m e d b y tw o la te r a l lo b e s w ith s u p e r io r a n d
in fe r io r p o le s c o n n e c te d b y a m e d ia n is th m u s , w ith a n a v e r a g e h e ig h t o f 1 2 to 1 5
m m , o v e r ly in g th e s e c o n d to fo u r th tr a c h e a l r in g s ( F ig u r e 3 ) . R a r e ly , th e is th -
m u s m a y b e a b s e n t, a n d th e g la n d e x is ts a s tw o d is tin c t lo b e s [ 1 9 ] . E a c h o f th e
la te r a l th y r o id lo b e s m e a s u r e s a n a v e r a g e o f 5 0 to 6 0 m m ( 8 to 1 0 m l in v o lu m e ) ,
w ith th e s u p e r io r p o le s d iv e r g in g la te r a lly a t th e le v e l o f th e o b liq u e lin e s o n th e
la m in a e o f th e th y r o id c a r tila g e ( F ig u r e 3 ) . T h e lo w e r p o le s d iv e r g e la te r a lly a t
th e le v e l o f th e fifth tr a c h e a l c a r tila g e . E v e n th o u g h th e w e ig h t o f th e th y r o id
g la n d v a r ie s , it a v e r a g e s b e tw e e n 1 5 g to 3 0 g in a d u lts a n d it is s o m e w h a t h e a v ie r
in w o m e n [ 1 0 ] [ 1 8 ] [ 1 9 ] . T h e th y r o id g la n d in c r e a s e s in s iz e d u r in g m e n s tr u a -
tio n a n d p r e g n a n c y [ 1 8 ] .
A p y r a m id a l lo b e w h ic h is p r e s e n t in a p p r o x im a te ly 5 0 % o f in d iv id u a ls o fte n
a sc e n d s fro m th e is th m u s o r th e a d ja c e n t p a r t o f e ith e r th y r o id lo b e ( m o r e o fte n
th e le ft) to w a r d th e h y o id b o n e , to w h ic h it m a y b e a tta c h e d b y a fib r o u s o r fib r o -
m u s c u la r b a n d , th e le v a to r o f th e th y r o id g la n d [ 1 9 ] . R e m n a n ts o f th e th y r o g lo s s a l
F ig u r e 3 . T h e th y r o id g la n d a n d its a n a to m ic r e la tio n s h ip s .
R. Arrangoiz et al.
d u c t m a y e n d u r e a s a c c e s s o r y n o d u le s o r c y s ts o f th y r o id tis s u e b e tw e e n th e
is th m u s a n d th e fo r a m e n c e c u m o f th e to n g u e b a s e [ 8 ] [ 1 8 ] . U s u a lly , tw o p a ir s o f
p a r a th y r o id g la n d s lie in p r o x im ity to th e th y r o id g la n d .
T h e th y r o id g la n d lie s a d ja c e n t to th e c a r o tid s h e a th s a n d th e s te r n o c le id o -
m a s to id m u s c le s la te r a lly o n e a c h s id e . T h e la te r a l s u r fa c e o f th e th y r o id g la n d is
c o v e r e d b y th e s te r n o th y r o id m u s c le ( F ig u r e 2 ) , a n d its a tta c h m e n t to th e o b li-
q u e lin e o f th e la m in a o f th e th y r o id c a r tila g e p r e v e n ts th e s u p e r io r p o le fr o m
e x te n d in g s u p e r io r ly u n d e r th e th y r o h y o id m u s c le [ 8 ] [ 1 9 ] . M o r e a n te r io r ly a r e
th e s te r n o h y o id a n d s u p e r io r b e lly o f th e o m o h y o id m u s c le , c o v e r e d in fe r io r ly
b y th e a n te r io r b o r d e r o f th e s te r n o c le id o m a s to id m u s c le [ 1 8 ] . T h e s te r n o h y o id
a n d s te r n o th y r o id m u s c le s a r e jo in e d in th e m id lin e b y a n a v a s c u la r fa s c ia th a t
m u s t b e in c is e d to r e tr a c t th e s tr a p m u s c le la te r a lly in o r d e r to a c c e s s th e th y r o id
g la n d d u r in g th y r o id e c to m y [ 8 ] [ 1 8 ] . I f th e s tr a p m u s c le s a r e to b e tr a n s e c te d fo r
b e tte r e x p o s u r e , it s h o u ld b e p e r fo r m e d h ig h in th e n e c k , b e c a u s e th e m o to r
n e r v e s u p p ly fr o m th e a n s a c e r v ic a lis ( a n s a h y p o g lo s s i) e n te r s th e s e m u s c le s in -
fe r io r ly [ 1 0 ] .
T h e th y r o id g la n d is e n v e lo p e d b y a lo o s e ly c o n n e c tin g fa s c ia th a t is fo r m e d
fr o m th e p a r titio n o f th e d e e p c e r v ic a l fa s c ia in to a n te r io r a n d p o s te r io r d iv i-
s io n s [ 8 ] . T h e tr u e th y r o id c a p s u le , a ls o k n o w n a s th e v is c e r a l fa s c ia , is a th in
d e n s e ly a d h e r e n t fib r o u s la y e r th a t s e n d s o u t s e p ta th a t in v a g in a te in to th e
g la n d , fo r m in g p s e u d o - lo b u le s [ 8 ] . T h e v is c e r a l fa s c ia , a d iv is io n o f th e m id d le
la y e r o f d e e p c e r v ic a l fa s c ia , a tta c h e s th e th y r o id g la n d to th e la r y n g e a l- s k e le to n
[ 8 ] [ 1 8 ] [ 1 9 ] . T h is fa s c ia c o n d e n s a te s in to tw o s u s p e n s o r y lig a m e n ts , th e a n te r io r
a n d p o s te r io r s u s p e n s o r y lig a m e n ts [ 1 9 ] . T h e a n te r io r s u s p e n s o r y lig a m e n t e x -
te n d s fr o m th e s u p e r io r - m e d ia l a s p e c t o f e a c h th y r o id lo b e to th e c r ic o id a n d
th y r o id c a r tila g e . T h e p o s te r io r s u s p e n s o r y lig a m e n t ( B e r r y lig a m e n t) e x te n d s
fr o m th e p o s te r io r - m e d ia l a s p e c t o f th e g la n d to th e s id e o f th e c r ic o id c a r tila g e ,
a n d fir s t a n d s e c o n d tr a c h e a l r in g s [ 8 ] [ 1 0 ] [ 1 8 ] [ 1 9 ] . T h is fir m a tta c h m e n t o f th e
g la n d to th e la r y n g e a l- s k e le to n is r e s p o n s ib le fo r m o v e m e n t o f th e th y r o id g la n d
a n d r e la te d s tr u c tu r e s d u r in g s w a llo w in g .
O n its w a y to th e la r y n x , th e r e c u r r e n t la r y n g e a l n e r v e ( R L N ) u s u a lly p a s s e s
d e e p to th e p o s te r io r s u s p e n s o r y lig a m e n t ( B e r r y lig a m e n t) o r b e tw e e n th e m a in
lig a m e n t a n d its la te r a l le a f [ 1 9 ] . D e e p to th e lig a m e n t, b u t la te r a l to th e n e r v e , is
a p o s te r o m e d ia l p o r tio n o f th e th y r o id lo b e , w h ic h m a y b e o v e r lo o k e d d u r in g
th y r o id e c to m y .
V a s c u la r A n a to m y
T h e th y r o id g la n d a s w e ll a s th e a d r e n a l g la n d s h a s th e g r e a te s t b lo o d s u p p ly
p e r g ra m o f tis s u e [ 2 2 ] . T h e s ig n ific a n c e is th a t h e m o s ta s is is a m a jo r p r o b le m o f
th y r o id s u r g e r y , e s p e c ia lly in p a tie n ts w ith g o ite r . T h e a r te r ia l ir r ig a tio n to th e
th y r o id g la n d c o m e s fr o m tw o p a ir e d a r te r ie s , th e s u p e r io r a n d in fe r io r th y r o id
a r te r ie s a n d , s o m e tim e s , fr o m th e th y r o id e a im a [ 8 ] . T h e s e a r te r ie s h a v e a b u n -
d a n t c o lla te r a l a n a s to m o s e s w ith e a c h o th e r , ip s ila te r a lly a n d c o n tr a - la te r a lly
( F ig u r e 4 ) . T h e th y r o id im a is a s in g le v e s s e l th a t, w h e n p r e s e n t ( 1 % to 4 % o f
in d iv id u a ls ) , o r ig in a te s fr o m th e a o r tic a r c h o r th e in n o m in a te a r te r y a n d e n te r s
R. Arrangoiz et al.
th e th y r o id g la n d a t th e in fe r io r b o r d e r o f th e is th m u s [ 8 ] [ 1 8 ] [ 1 9 ] . I ts p o s itio n
a n te r io r to th e tr a c h e a m a k e s it im p o r ta n t in tr a c h e o s to m y .
T h e s u p e r io r th y r o id a r te r y is th e fir s t a n te r io r b r a n c h o f th e e x te r n a l c a r o tid
a r te r y [ 8 ] . I n r a r e c a s e s , it m a y a r is e fr o m th e c o m m o n c a r o tid a r te r y ju s t b e fo r e
its b ifu r c a tio n [ 8 ] [ 1 8 ] . T h e s u p e r io r th y r o id a r te r y p a s s e s d o w n w a r d a n d a n te -
r io r ly to r e a c h th e s u p e r io r p o le o f th e th y r o id g la n d u n d e r th e c o v e r o f th e s u -
p e r io r b e lly o f th e o m o h y o id a n d s te r n o h y o id m u s c le s . I n p a r t o f its tr a c k , th e
a r te r y p a r a lle ls th e e x te r n a l b r a n c h o f th e s u p e r io r la r y n g e a l n e r v e ( S L N ) w h ic h
s u p p lie s th e c r ic o th y r o id m u s c le a n d th e c r ic o p h a r y n g e u s m u s c le , th e lo w e s t
v o lu n ta r y p a r t o f th e p h a r y n g e a l m u s c u la tu r e [ 8 ] . T h e a r te r y r u n s s u p e r fic ia lly o n
th e a n te r io r b o r d e r o f th e la te r a l lo b e , d iv id in g in to a n te r io r a n d p o s te r io r
b r a n c h e s a t th e a p ic e s o f th e th y r o id lo b e s . T h e s e b r a n c h e s s e n d b r a n c h e s ( te r m in -
a l) d e e p in to th e th y r o id g la n d b e fo r e c u r v in g to w a r d th e is th m u s , w h e r e th e y
a n a s to m o s e w ith th e c o n tr a la te r a l a r te r y ( u s u a lly th e a n te r io r b r a n c h ) [ 8 ] [ 1 9 ] .
T h e s u p e r io r th y r o id a r te r y h a s s ix b r a n c h e s : th e in fr a h y o id , s te r n o c le id o -
m a s to id , s u p e r io r la r y n g e a l, c r ic o th y r o id , in fe r io r p h a r y n g e a l c o n s tr ic to r , a n d
te r m in a l b r a n c h e s o f th e a r te r y fo r th e s u p p ly o f th e th y r o id a n d p a r a th y r o id
g la n d s [ 8 ] . T h e r e a r e u s u a lly tw o b r a n c h e s to th e th y r o id g la n d ( a n te r io r a n d
p o s te r io r ) b u t in r a r e in s ta n c e s th e r e m a y b e a th ir d b r a n c h , th e s o - c a lle d la te r a l
b r a n c h [ 8 ] ( F ig u r e 4 a n d F ig u r e 5 ) . T h e a n te r io r b r a n c h a n a s to m o s e s w ith th e
c o n tr a la te r a l a r te r y [ 2 3 ] , th e p o s te r io r b r a n c h a n a s to m o s e s w ith th e ip s ila te r a l
in fe r io r th y r o id a r te r y [ 8 ] . T h e p o s te r io r b r a n c h g iv e s o ff a s m a ll p a r a th y r o id a r -
te r y w h ic h s u p p lie s th e s u p e r io r p a r a th y r o id g la n d in 4 5 % o f th e c a se s [8 ] [2 4 ].
N o b o r i e t a l. [ 2 4 ] n o te d th a t in 6 7 % o f th e c a s e s th e s u p e r io r p a r a th y r o id g la n d s
r e c e iv e d th e ir b lo o d s u p p ly fr o m a s in g le v e s s e l, a n d in 1 /3 o f th e c a s e s tw o o r
m o r e b r a n c h e s r e a c h e d th e s u p e r io r p a r a th y r o id g la n d s .
H ig h lig a tio n o f th e s u p e r io r th y r o id a r te r y d u r in g th y r o id e c to m y p la c e s th e
e x te rn a l b ra n c h o f th e S L N a t r is k o f in a d v e r te n t in ju r y , w h ic h w o u ld p r o d u c e
d y s p h o n ia b y a lte r in g p itc h r e g u la tio n [ 2 5 ] . T h e c r ic o th y r o id a r te r y , a p o te n tia l-
ly tr o u b le s o m e b r a n c h o f th e s u p e r io r th y r o id a r te r y , r u n s s u p e r io r to th e u p p e r
F ig u r e 4 . A r te r ia l s u p p ly o f th e th y r o id g la n d a n d v e n o u s d r a in a g e o f th e th y r o id g la n d .
R. Arrangoiz et al.
F ig u r e 5 . A n a to m y o f th e r e c u r r e n t la r y n g e a l n e r v e a n d its r e la tio n s h ip o f th e in fe r io r th y r o id a r te r y a n d r e c u r r e n t la r y n g e a l
n e rv e .
p o le a n d r u n s to w a r d th e m id lin e o n th e c r ic o th y r o id lig a m e n t [ 8 ] . T h is v e s s e l
c a n b e la c e r a te d d u r in g e m e r g e n t c r ic o th y r o id o to m y .
T h e in fe r io r th y r o id a r te r y u s u a lly a r is e s fr o m th e th y r o c e r v ic a l tr u n k ( F ig u r e
4 ) , a b r a n c h o f th e s u b c la v ia n a r te r y [ 1 8 ] [ 1 9 ] , b u t in 1 5 % o f in d iv id u a ls it m a y
a r is e fr o m th e s u b c la v ia n a r te r y [ 8 ] . T h e in fe r io r th y r o id a r te r y a s c e n d s v e r tic a lly
b e h in d th e c a r o tid s h e a th c u r v in g m e d ia lly a n d p o s te r io r ly o n th e a n te r io r s u r -
fa c e o f th e lo n g u s c o li m u s c le b e fo r e e n te r in g th e tr a c h e o e s o p h a g e a l g r o o v e [ 8 ]
[ 1 8 ] [ 1 9 ] . A fte r p e n e tr a tin g th e p r e v e r te b r a l fa s c ia , th e a r te r y d iv id e s in to tw o o r
m o r e b r a n c h e s a s it c r o s s e s th e R L N . T h e lo w e s t b r a n c h s e n d s a tin n y b r a n c h to
s u p p ly th e in fe r io r p a r a th y r o id g la n d a n d s u p p lie s th e lo w e r p o le o f th e th y r o id
g la n d [ 8 ] . T h e u p p e r b r a n c h o f th e in fe r io r th y r o id a r te r y s u p p lie s th e p o s te r io r
s u r fa c e o f th e g la n d , u s u a lly a n a s to m o s in g w ith th e d e s c e n d in g b r a n c h o f th e
s u p e r io r th y r o id a r te r y ( p o s te r io r b r a n c h ) [ 8 ] . O n th e r ig h t- h a n d s id e th e in fe -
r io r th y r o id a r te r y is a b s e n t in a p p r o x im a te ly 2 % o f in d iv id u a ls , o n th e le ft- h a n d
s id e it is a b s e n t in 5 % o f th e c a s e s [ 8 ] [ 2 6 ] . A d u p lic a te d a r te r y is a r a r e o c c u r -
re n c e [2 7 ].
T h e R L N a s c e n d s in th e tr a c h e o e s o p h a g e a l g r o o v e a n d e n te r s th e la r y n x b e -
tw e e n th e in fe r io r c o r n u o f th e th y r o id c a r tila g e a n d th e a r c h o f th e c r ic o id c a r -
tila g e [ 1 8 ] [ 1 9 ] ( F ig u r e 5 ) . T h e R L N c a n b e fo u n d a fte r it e m e r g e s fr o m th e su -
p e r io r th o r a c ic o u tle t, in a tr ia n g le b o u n d e d la te r a lly b y th e c o m m o n c a r o tid a r -
te r y , m e d ia lly b y th e tr a c h e a , a n d s u p e r io r ly b y th e th y r o id lo b e . T h e r e la tio n -
s h ip b e tw e e n th e in fe r io r th y r o id a r te r y a n d th e R L N is h ig h ly v a r ia b le , a s e s ta b -
lis h e d b y th e w o r k o f R e e d A .F . [ 2 8 ] , w h o in 1 9 4 3 d e s c r ib e d 2 8 v a r ia tio n s in th is
r e la tio n s h ip . T h e R L N c a n b e fo u n d d e e p to th e in fe r io r th y r o id a r te r y ( 4 0 % o f
th e c a s e s ) , s u p e r fic ia l to th e R L N (2 0 % o f th e c a se s), o r b e tw e e n th e b ra n c h e s o f
th e in fe r io r th y r o id a r te r y ( 3 5 % o f th e c a s e s ) [ 2 8 ] [ 2 9 ] [ 3 0 ] . N o ta b ly , th e a s s o c ia -
tio n b e tw e e n th e R L N a n d th e in fe r io r th y r o id a r te r y o n o n e s id e o f th e n e c k is
c o m p a r a b le to th a t fo u n d o n th e o th e r s id e in o n ly 1 7 % o f in d iv id u a ls [ 2 8 ] . F u r -
th e r m o r e , a t th e le v e l o f th e in fe r io r th y r o id a r te r y , b r a n c h e s o f th e R L N th a t a re
R. Arrangoiz et al.
e x tr a la r y n g e a l m a y b e p r e s e n t in 5 % o f th e c a s e s [ 1 8 ] [ 2 8 ] [ 2 9 ] . P r e s e r v a tio n o f
a ll o f th o s e b r a n c h e s is v e r y im p o r ta n t d u r in g th y r o id s u r g e r y .
V e in s o f th e th y r o id g la n d fo r m a p le x u s o f v e s s e ls ly in g in th e s u b s ta n c e a n d
o n th e s u r fa c e o f th e g la n d [ 1 9 ] . T h e p le x u s is d r a in e d b y th r e e p a ir s o f v e in s th a t
p r o v id e v e n o u s d r a in a g e fo r th e th y r o id ( F ig u r e 4 ) . T h e s u p e r io r th y r o id v e in
a c c o m p a n ie s th e s u p e r io r th y r o id a r te r y . A s it e m e r g e s fr o m th e s u p e r io r p o le o f
th e th y r o id g la n d , th e v e in p a s s e s s u p e r io r ly a n d la te r a lly a c r o s s th e s u p e r io r
b e lly o f th e o m o h y o id m u s c le a n d th e c o m m o n c a r o tid a r te r y to e n te r th e in te r -
n a l ju g u la r v e in a lo n e o r w ith th e c o m m o n fa c ia l v e in [ 8 ] . T h e m id d le th y r o id
v e in a r is e s o n th e la te r a l s u r fa c e o f th e th y r o id g la n d a t a b o u t tw o - th ir d s o f its
a n te r o p o s te r io r e x te n t. I t c r o s s e s th e c o m m o n c a r o tid a r te r y fo llo w in g a d ir e c t
c o u r s e to th e in te r n a l ju g u la r v e in ( n o a r te r y e s c o r ts it) [ 8 ] [ 1 8 ] . T h is v e in m a y
b e a b s e n t o r , in v e r y r a r e o c c u r r e n c e s it m a y b e d o u b le [ 8 ] . T h e e x tr a v e in is in -
fe r io r to th e n o r m a l v e in ( fo u r th th y r o id v e in ) . T h e im p o r ta n c e o f th e s e th y r o id
v e in s is in th e ir v u ln e r a b ility d u r in g th y r o id s u r g e r y . T h e in fe r io r th y r o id v e in s
a r e th e la r g e s t a n d m o s t v a r ia b le o f th e th y r o id v e in s ( th e r ig h t a n d le ft s id e a r e
u s u a lly a s y m m e tr ic ) [ 8 ] . T h e y fo llo w d iffe r e n t p a th w a y s o n e a c h s id e . T h e r ig h t
in fe r io r th y r o id v e in p a s s e s a n te r io r to th e in n o m in a te a r te r y to d r a in in to th e
r ig h t b r a c h io c e p h a lic v e in , r a r e ly in m a y c r o s s a n te r io r to th e tr a c h e a a n d d r a in
in to th e le ft b r a c h io c e p h a lic v e in [ 1 8 ] . T h e le ft v e in c r o s s e s th e tr a c h e a to e n te r
th e le ft b r a c h io c e p h a lic v e in [ 1 8 ] . S p o r a d ic a lly , b o th in fe r io r th y r o id v e in s fo r m
a c o m m o n tr u n k c a lle d th e th y r o id im a v e in , w h ic h e m p tie s in to th e le ft b r a c h i-
o c e p h a lic v e in [ 8 ] [ 1 8 ] [ 1 9 ] .
L y m p h a tic A n a to m y
T h e ly m p h a tic d r a in a g e o f th e th y r o id g la n d is e x te n s iv e a n d flo w s in a m u lti-
d ir e c tio n a l p a tte r n (F ig u r e 6 ). T h e H o llin s h e a d p a tte r n o f d r a in a g e is d iv id e d
in to fo u r d is tin c t p a tte r n s: m e d ia n s u p e r io r d r a in a g e , m e d ia n in fe r io r d r a in a g e ,
r ig h t/le ft la te r a l d r a in a g e , a n d p o ste r io r d r a in a g e [ 8 ] [3 1 ].
T h e m e d ia n s u p e r io r d r a in a g e is th r o u g h th r e e to s ix ly m p h a tic v e s s e ls th a t
a r is e fr o m th e s u p e r io r m a r g in o f th e is th m u s a n d fr o m th e u p p e r m e d ia l m a r -
g in o f th e la te r a l lo b e s . T h e s e ly m p h a tic v e s s e ls tr a v e l u p w a r d s to w a r d s th e la -
r y n x to e n d u p in th e d ia g a s tr ic n o d e s . S o m e o f th e ly m p h a tic s m a y d r a in in to
o n e o r tw o o f th e p r e - la r y n g e a l ( D e lp h ia n ) n o d e s ju s t a b o v e th e is th m u s [ 8 ] [ 3 1 ] .
T h e s e c o n d a r y e c h e lo n is to th e u p p e r ju g u la r n o d e s o n e ith e r s id e o f th e n e c k o r
to p r e - tr a c h e a l n o d e s b e lo w th e th y r o id th r o u g h ly m p h a tic c h a n n e ls th a t tr a v e l
fro m th e D e lp h ia n n o d e s d o w n w a r d o v e r th e a n te r io r a s p e c t o f th e th y r o id g la n d
[8 ] [3 1 ].
T h e m e d ia n in fe r io r d r a in a g e o c c u r s th r o u g h s e v e r a l ly m p h a tic s v e s s e ls th a t
d r a in th e in fe r io r a s p e c t o f th e is th m u s a n d th e lo w e r m e d ia l p o r tio n s o f th e la t-
e r a l lo b e s [ 9 ] [ 3 1 ] . T h e s e s ly m p h a tic s c h a n n e ls fo llo w th e in fe r io r th y r o id v e in s
to e n d in th e p r e - tr a c h e a l a n d b r a c h io c e p h a lic n o d e s [ 8 ] [ 1 8 ] . T h e r ig h t a n d le ft
la te r a l d r a in a g e p a tte r n o r ig in a te fr o m ly m p h a tic tr u n k s fr o m th e la te r a l b o r d e r
o f e a c h lo b e [ 8 ] [ 3 1 ] . S u p e r io r ly th e a s c e n d w ith th e s u p e r io r th y r o id a r te r y a n d
v e in , in fe r io r ly th e y fo llo w th e in fe r io r th y r o id a r te r y [ 1 8 ] [ 3 1 ] . B e tw e e n th e s e
R. Arrangoiz et al.
F ig u r e 6 . T h e ly m p h a tic d r a in a g e o f th e th y r o id g la n d is e x te n s iv e a n d flo w s in a m u lti-

d ir e c tio n a l p a tte r n .
tw o g r o u p s , th e ly m p h a tic c h a n n e ls tr a v e l la te r a lly , a n te r io r ly , o r p o s te r io r ly to
th e c a r o tid s h e a th to r e a c h th e ly m p h n o d e s o f th e in te r n a l ju g u la r v e in [ 8 ] [ 1 8 ]
[ 1 9 ] [ 3 1 ] . I n r a r e in s ta n c e s th e s e ly m p h a tic v e s s e ls d r a in d ir e c tly in to th e s u b -
c la v ia n v e in , ju g u la r v e in , o r th o r a c ic d u c t w ith o u t c ir c u la tin g th r o u g h a ly m p h
n o d e [3 2 ].
T h e p o s te r io r d r a in a g e p a tte r n o c c u r s th r o u g h ly m p h a tic v e s s e ls th a t d r a in
th e in fe r o m e d ia l s u r fa c e s o f th e la te r a l lo b e s to d r a in in to ly m p h n o d e s a lo n g th e
tra c k o f th e R L N [ 8 ] [ 3 1 ] . O c c a s io n a lly , a p o s te r io r a s c e n d in g ly m p h a tic tr u n k
fro m th e u p p e r p a r t o f th e lo b e r e a c h e s th e r e tr o p h a r y n g e a l n o d e s [ 3 1 ] .
S e v e r a l p a tte r n s o f ly m p h a tic d r a in a g e o f th e th y r o id g la n d h a v e b e e n p r o -
p o s e d , e a c h is c o r r e c t a n d c o n c e p tu a liz e d fr o m th e s a m e fa c t. A n o th e r s im p lifie d
p a tte r n o f d r a in a g e is th e fo llo w in g : im m e d ia te ly m p h a tic d r a in a g e g o e s to th e
p e r i- g la n d u la r n o d e s ; to th e p r e - la r y n g e a l ( D e lp h ia n ) , p r e - tr a c h e a l, a n d p a r a - tr a c h e a l
n o d e s a lo n g th e R L N ; a n d th e n to m e d ia s tin a l ly m p h n o d e s [ 1 8 ] [ 1 9 ] . R e g io n a l
m e ta s ta s e s o f th y r o id c a n c e r c a n a ls o b e fo u n d la te r a lly , h ig h e r in th e n e c k a lo n g
th e in te r n a l ju g u la r v e in . T h is c a n b e e x p la in e d b y tu m o r in v a s io n o f th e
p r e - tr a c h e a l a n d p a r a - tr a c h e a l n o d e s c a u s in g a n o b s tr u c tio n o f n o r m a l ly m p h
flo w .
I n n e r v a tio n o f th e th y r o id g la n d
T h e th y r o id g la n d is in n e r v a te d b y th e a u to n o m ic n e r v o u s s y s te m (A N S ). T h e
s y m p a th e tic in n e r v a tio n o f th e th y r o id g la n d is th r o u g h th e s u p e r io r , m id d le ,
a n d in fe r io r g a n g lia o f th e c e r v ic a l c h a in [ 8 ] . I n th y r o id s u r g e r y th e s u p e r io r la -
ry n g e a l n e rv e a n d th e R L N ( p a r a s y m p a th e tic /v a g u s ) , w h ic h d o n o t in n e r v a te th e
th y r o id g la n d , a r e o f e x tr e m e im p o r ta n c e . T h e r is k o f in ju r y to th e R L N is d i-
R. Arrangoiz et al.
r e c tly r e la te d to th e le v e l o f k n o w le d g e a b o u t th e a n a to m y o f th e h e a d a n d n e c k
a n d th e e x p e r tis e o f th e h e a d a n d n e c k s u r g e o n . T h e fu n c tio n s o f th e la r y n x a r e
to p r o te c t th e lo w e r a ir w a y , p h o n a tio n , a n d g e n e r a tio n o f a h ig h in tr a th o r a c ic
p r e s s u r e fo r c o u g h in g a n d liftin g [ 3 3 ] .
T h e R L N ( in fe r io r la r y n g e a l n e r v e s ) o r ig in a te fr o m th e V I b r a n c h ia l a r c h [ 3 3 ] .
T h e s e n e r v e s a r is e fr o m th e v a g u s n e r v e s u n d e r th e V I a o r tic a r c h . A fte r w a r d s
th e V a n d th e d is ta l p o r tio n o f th e V I a o r tic a r c h r e g r e s s , o n b o th th e r ig h t a n d
le ft s id e , a n d th e tw o la r y n g e a l n e r v e s r e m a in s a tta c h e d to th e s tr u c tu r e s th a t
d e v e lo p fr o m th e IV a o r t ic a r c h ( i.e ., t h e r ig h t s u b c la v ia n a r t e r y a n d t h e a o r t ic
a r c h o n th e le ft s id e ) . A s th e h e a r t d e s c e n d s in to th e th o r a x , th e s e a r te r ie s ta k e
w ith th e m th e n e r v e s , w h ic h th e n a s s u m e th e ir n o r m a l r e c u r r e n t c o u r s e ( F ig u r e
5 ).
G a le n w a s th e fir s t to d o c u m e n t th e p r e s e n c e o f th e R L N a n d h e w a s a ls o th e
fir s t to e s ta b lis h th a t th e fu n c tio n o f th e la r y n x w a s to g e n e r a te v o ic e [ 3 4 ] . T h e
R L N is v a r ia b le in s iz e r a n g in g fr o m 1 .5 m m to 4 m m in d ia m e te r [ 1 2 ] . M a c r o s -
c o p ic a lly th e R L N is w h itis h in a p p e a r a n c e a n d c a n h a v e a fla tte n e d o r r o u n d e d
su rfa c e [8 ] [1 2 ] [1 8 ] [1 9 ] (F ig u r e 5 ). T h e R L N p r e d o m in a n tly p r o v id e s th e m o -
to r s u p p ly to th e in tr in s ic la r y n g e a l m u s c le s a n d s e n s o r y in n e r v a tio n to th e in -
fr a g lo ttis [ 3 5 ] . T h e s u p e r io r la r y n g e a l n e r v e ( S L N ) p r e d o m in a n tly p r o v id e s th e
s e n s o r y s u p p ly to th e s u p r a g lo ttis a n d g lo ttis , b u t its e x te r n a l b r a n c h a ls o p r o -
v id e s th e m o to r s u p p ly to th e c r ic o th y r o id m u s c le [ 3 6 ] . T h e a n s a G a le n i, a n
a n a s t o m o s is b e t w e e n t h e S L N ’s in t e r n a l b r a n c h a n d o n e o f t h e R L N ’s b r a n c h e s
( u s u a lly th e p o s te r io r b r a n c h o f th e R L N c o n tr ib u te s to th e a n a s to m o s is ; h o w e v -
e r , th e a n te r io r b r a n c h c a n a ls o c o n tr ib u te ) , p r o v id e s th e a c c e s s o r y m o to r a n d
p r e d o m in a n t s e n s o r y s u p p ly to e n d o la r y n g e a l s tr u c tu r e s [ 3 6 ] . T h e “ h u m a n
c o m m u n ic a tin g n e r v e ” ( H C N ) is a n a n a s to m o s is b e tw e e n th e e x te r n a l b r a n c h o f
th e S L N a n d th e d is ta l R L N , it is fo u n d in a p p r o x im a te ly 3 % to 6 8 % o f th e c a se s
[3 7 ] [3 8 ] [3 9 ]. T h e H C N m a y c o n ta in b o th s e n s o r y in n e r v a tio n to th e la r y n x a n d
m o to r in n e r v a tio n to th e th y r o a r y te n o id m u s c le [ 3 7 ] [ 3 8 ] [ 3 9 ] .
T h e r ig h t R L N b ra n c h e s fro m th e v a g u s n e r v e ( c r a n ia l n e r v e X ) a s it c r o s s e s
a n te r io r to th e r ig h t s u b c la v ia n a r te r y , lo o p in g a r o u n d th e s u b c la v ia n a rte ry
fro m p o s te r io r to a n te r io r , p a s s in g b e h in d th e r ig h t c a r o tid s h e a th a n d a s c e n d in g
in th e r ig h t tr a c h e o e s o p h a g e a l g r o o v e [ 8 ] . It c o u r s e s p o s te r io r to th e r ig h t th y -
r o id lo b e to e n te r th e la r y n x b e h in d th e c r ic o th y r o id a r tic u la tio n a n d th e in fe r io r
c o r n u o f th e th y r o id c a r tila g e ( F ig u r e 5 ) . T h e le ft R L N o r ig in a te s fr o m th e le ft
v a g u s n e r v e a t th e p o in t w h e r e th e n e r v e c r o s s e s th e a o r tic a r c h , lo o p in g u n d e r
th e lig a m e n tu m a r te r io s u m a n d th e a o r ta , a s c e n d in g in th e le ft tr a c h e o e s o p h a -
g e a l g r o o v e [ 8 ] . B o th n e r v e s c r o s s th e in fe r io r th y r o id a r te r ie s n e a r th e lo w e r
b o r d e r o f th e m id d le th ir d o f th e g la n d .
T h e e n tr y p o in t o f th e R L N in to th e la r y n x is ju s t b e h in d a n d b e lo w th e c r ic o -
th y r o id jo in t [ 8 ] . A t th is le v e l, it is p r o te c te d b y th e in fe r io r p h a r y n g e a l c o n -
s tr ic to r m u s c le a n d th e c r ic o th y r o id m u s c le [ 4 0 ] . I n a p p r o x im a te ly 9 0 % o f th e
c a se s, th e R L N d iv id e s in to tw o to th r e e b r a n c h e s ju s t a fe w m illim e te r s b e fo r e
R. Arrangoiz et al.
e n te r in g th e la r y n x u n d e r n e a th th e in fe r io r p h a r y n g e a l c o n s tr ic to r m u s c le [ 4 0 ] .
T h e b r a n c h in g o f th e R L N o u ts id e th e la r y n x c a n o c c u r a t a n y p o in t a lo n g th e
c o u r s e o f th e n e r v e b u t it is u n u s u a l b e lo w th e in fe r io r th y r o id a r te r y [ 4 1 ] . C la s -
s ic a lly , th e e x tr a la r y n g e a l b r a n c h e s o f th e R L N w e r e d e s c r ib e d a s fu n c tio n a lly
d is c r e te fib e r s , s e p a r a te d in to th e a n te r io r a n d p o s te r io r b r a n c h e s , w h e r e th e a n -
te r io r b r a n c h e s e x c lu s iv e ly in n e r v a te d th e a d d u c to r m u s c le s ( la te r a l c r ic o a r y te -
n o id , in te r a r y te n o id , a n d th y r o a r y te n o id ) , w h e r e a s th e p o s te r io r b r a n c h e s in -
n e r v a te d th e a b d u c to r m u s c le s ( p o s te r io r c r ic o a r y te n o id ) [ 4 2 ] [ 4 3 ] . N e v e r th e -
le s s , o th e r s tu d ie s h a v e d e s c r ib e d n o c o n s is te n t fu n c tio n a l p a tte r n o f b r a n c h in g
o f th e a n te r io r a n d p o s te r io r la r y n g e a l b r a n c h e s [ 4 2 ] [ 4 3 ] .
T h e R L N in n e r v a te s th e fo u r in tr in s ic m u s c le s o f th e la r y n x ( la te r a l c r ic o a r y -
te n o id , p o s te r io r c r ic o a r y te n o id , tr a n s v e r s e a n d o b liq u e in te r a r y te n o id a n d th y -
r o a r y te n o id ) b u t it d o e s n o t p r o v id e in n e r v a tio n to th e c r ic o th y r o id m u s c le
( F ig u r e 7 ) [ 8 ] [ 1 8 ] [ 1 9 ] [ 3 0 ] . T h e in te r a r y te n o id m u s c le , th e o n ly u n p a ir e d m u s -
c le o f th e la r y n x , r e c e iv e s in n e r v a tio n fr o m b o th R L N s [ 3 0 ] [ 4 0 ] . B e fo r e e n te r in g
th e la r y n x , th e R L N a ls o s e n d s b r a n c h e s to th e in fe r io r p h a r y n g e a l c o n s tr ic to r
m u s c le a n d c r ic o p h a r y n g e u s m u s c le [ 8 ] [ 1 8 ] [ 1 9 ] [ 3 0 ] [ 4 0 ] . A s m e n tio n e d p r e -
v io u s ly th e R L N p r o v id e s s e n s o r y in n e r v a tio n to th e m u c o s a o f th e in fr a g lo ttis
[3 6 ].
T h e R L N is a t r is k o f in ju r y d u r in g th y r o id s u r g e r ie s . E v e n th o u g h d is a g r e e -
m e n t s till s u r r o u n d s w h e th e r th e r e c o g n itio n o f th e R L N d u r in g th y r o id s u r g e r y
w ill in flu e n c e th e in c id e n c e in ju r y , m o s t s u r g e o n s e n c o u r a g e th e id e n tific a tio n
a n d d is s e c tio n o f th e n e r v e d u r in g th e p r o c e d u r e to r e d u c e th e r is k o f in ju r y
[ 4 1 ] . S o m e s u r g ic a l la n d m a r k s h a v e b e e n re c o m m e n d e d to id e n tify th e R L N
d u r in g th y r o id s u r g e r y , in c lu d in g th e r e la tio n o f th e n e r v e to in fe r io r th y r o id
a r te r y , th e r e la tio n o f th e R L N to th e tr a c h e o e s o p h a g e a l g r o o v e , th e r e la tio n o f
th e R L N t o B e r r y ’s lig a m e n t , a n d t h e r e la t io n o f t h e n e r v e t o Z u c k e r k a n d l’s t u -
b e r c le .
T h e a s s o c ia tio n th a t e x is ts b e tw e e n th e R L N a n d in fe r io r th y r o id a r te r y is v a -
r ia b le [ 4 4 ] [ 4 5 ] . A s m e n tio n e d p r e v io u s ly R e e d A .F . [ 2 8 ] d e s c r ib e d 2 8 v a r ia tio n s
in th is r e la tio n s h ip . I n h is p a p e r th e R L N c a n b e fo u n d d e e p to th e in fe r io r th y -
r o id a r te r y ( 4 0 % o f th e c a s e s ) , s u p e r fic ia l to th e R L N (2 0 % o f th e c a se s), o r b e -
tw e e n th e b r a n c h e s o f th e in fe r io r th y r o id a r te r y ( 3 5 % o f th e c a se s) [2 8 ] [2 9 ]
[ 3 0 ] . N o ta b ly , th e a s s o c ia tio n b e tw e e n th e R L N a n d th e in fe r io r th y r o id a r te r y
o n o n e s id e o f th e n e c k is c o m p a r a b le to th a t fo u n d o n th e o th e r s id e in o n ly
1 7 % o f in d iv id u a ls [ 2 8 ] . S te in b e r g e t a l. [ 4 4 ] r e p o r te d th a t th e R L N c o u r se s in
th e n e c k b e tw e e n th e b r a n c h e s o f th e in fe r io r th y r o id a r te r y in a b o u t 6 .5 % o f in -
d iv id u a ls , p o s te r io r to th e in fe r io r th y r o id a r te r y in 6 1 .5 % o f in d iv id u a ls , a n d
a n te r io r to th e in fe r io r t h y r o id a r te r y in 3 2 .5 % . O n th e r ig h t - h a n d s id e , th e R L N
m a y b e in a n y o f th r e e lo c a tio n s in r e la tio n to th e a r te r y [ 4 4 ] [ 4 5 ] ( F ig u r e 8 ) . O n
th e le ft- h a n d s id e , it is m o r e lik e ly to lie p o s te r io r to th e a r te r y [ 4 4 ] [ 4 5 ] ( F ig u r e 8 ) .
T h e R L N is c o m m o n ly fo u n d n e a r t h e p o s t e r io r s u s p e n s o r y lig a m e n t ( B e r r y ’s
lig a m e n t) , w ith th e v a s t m a jo r ity o f th e n e r v e s fo u n d w ith in th r e e m illim e te r s
R. Arrangoiz et al.
F ig u r e 7 . In tr in s ic m u s c le s o f th e la r y n x .
R. Arrangoiz et al.
F ig u r e 8 . V a r ia n ts in th e a s s o c ia tio n b e tw e e n in fe r io r th y r o id a r te r y a n d R L N a n d th e R L N fo u n d p o s te r io r to th e p o s te r io r s u s -
p e n s o r y lig a m e n t.
[ 3 5 ] . T h e r e h a v e b e e n s o m e d e s c r ip tio n s w e r e th e R L N p e n e tra te s th ro u g h th e
p o s te r io r s u s p e n s o r y lig a m e n t [ 8 ] [ 4 6 ] ( F ig u r e 8 ) , b u t in th e m a jo r ity o f c a s e s
( 4 5 % ) , t h e R L N is s u p e r f ic ia l ( d o r s o la t e r a l) t o t h e B e r r y ’s lig a m e n t [ 4 7 ] .
T h e d is ta l e n d o f th e R L N c a n b e s e e n a lo n g th e tr a c t o f th e tr a c h e o e s o p h a g e a l
g r o o v e [ 3 0 ] . T h e R L N c a n b e lo c a liz e d m o r e r e lia b ly a t th e c r ic o th y r o id a r tic u la -
tio n . S h in d o e t a l. [ 3 0 ] r e p o r te d th a t m o s t o f th e R L N s o n th e r ig h t- h a n d s id e
c o u r s e b e tw e e n 1 5 ˚ to 4 5 ˚ w h e n e n te r in g th e c r ic o th y r o id jo in t, w h ile m o s t o f
th e R L N s o n th e le ft- h a n d s id e c o u r s e b e tw e e n 0 ˚ to 3 0 ˚ , th is d iffe r e n c e is s e c -
o n d a r y to th e m o r e a n g le d tr a c k th e r ig h t R L N ta k e s w h e n a s c e n d in g in th e
n e c k . T h e m o s t c o m m o n d ir e c tio n o f th e r ig h t a n d le ft R L N w a s ty p e I I ( 1 5 ˚ to
3 0 ˚ ) , th e n e x t c o m m o n r o u te o n th e r ig h t h a n d - s id e w a s a ty p e III ( 3 0 ˚ to 4 5 ˚ )
a n d o n th e le ft- h a n d s id e w a s a ty p e I ( 0 ˚ to 1 5 ˚ ) [ 3 0 ] .
T h e tu b e r c le o f Z u c k e r k a n d l is c h a r a c te r iz e d a s b e in g a th ic k e n in g in th e th y -
r o id g la n d w h e r e th e u ltim o b r a n c h ia l b o d y m e r g e s w ith th e m e d ia n th y r o id a n -
la g e a n d c a n e n la r g e d to b e c o m e a n o d u la r p r o c e s s [ 4 8 ] . W h e n e n la r g e d , it is a
r e lia b le la n d m a r k fo r th e R L N b e c a u s e th e n e r v e a lm o s t a lw a y s c o u r s e s m e d ia l
a n d d e e p to it [ 1 5 ] .
A n o n - r e c u r r e n t la r y n g e a l n e r v e is a v e r y r a r e fin d in g , 0 .5 % t o 1 % o f t h e c a s e s
[ 8 ] [ 1 8 ] [ 1 9 ] [ 3 5 ] . I t is a s s o c ia te d w ith a n a b e r r a n t r ig h t s u b c la v ia n a r te r y , a r is -
in g fr o m th e a o r ta a fte r th e le ft s u b c la v ia n a r te r y h a s g iv e n o ff [ 8 ] . I n th e s e c ir -
c u m s ta n c e s th e r ig h t R L N p a s s e s d ir e c tly fr o m th e v a g u s n e r v e in th e n e c k to -
w a r d s th e la r y n x a n d d o e s n o t r e c u r a r o u n d s u b c la v ia n a r te r y ( F ig u r e 9 ) . T h is
u n c o m m o n a n a to m ic v a r ia tio n o f th e r ig h t R L N m a k e s it h ig h ly s u s c e p tib le to
s u r g ic a l in ju r y . A le ft n o n - r e c u r r e n t la r y n g e a l n e r v e is e x tr e m e ly r a r e [ 8 ] .
T h e S L N a r is e s fr o m th e v a g u s n e r v e b e lo w its lo w e r s e n s o r y g a n g lio n ( in fe -
r io r g a n g lio n ) ju s t o u ts id e th e ju g u la r fo r a m e n o f th e s k u ll [ 8 ] . T h e n e r v e d e s -
c e n d s la te r a l to th e p h a r y n x , a t fir s t p o s te r io r a n d th e n m e d ia l to th e in te r n a l
c a r o tid a r te r y ( I C A ) . A t th e le v e l o f g r e a te r c o r n u o f h y o id b o n e , th e S L N d iv id e s
in to a s m a lle r e x te r n a l b r a n c h ( m o to r ) a n d a la r g e r in te r n a l b r a n c h ( s e n s o r y ) [ 8 ]
[ 4 9 ] . T h e p o in t o f d iv is io n is u s u a lly w ith in th e b ifu r c a tio n o f th e c o m m o n
R. Arrangoiz et al.
F ig u r e 9 . A n o n - r e c u r r e n t la r y n g e a l n e r v e o r ig in a tin g fr o m th e v a g u s n e r v e a b o v e a n d b e lo w th e la r y n g e a l
tr a c h e a l ju n c tio n .
F ig u r e 1 0 . B r a n c h in g o f th e s u p e r io r la r y n g e a l n e r v e ( S L N ) .
c a r o tid a r te r y ( F ig u r e 1 0 ) .
T h e la r g e r in te r n a l b r a n c h o f th e S L N c r o s s e s th e e x te r n a l c a r o tid a r te r y a b o v e
o r b e lo w th e o r ig in o f th e lin g u a l a r te r y , o r in r a r e c a s e s th e n e r v e m a y d iv id e
m e d ia l to th e e x te r n a l c a r o tid a r te r y [ 5 0 ] . T h e in te r n a l b r a n c h o f th e S L N p ie r c e s
th e th y r o h y o id m e m b ra n e a b o v e th e e n tra n c e o f s u p e r io r la r y n g e a l a r te r y
( b r a n c h o f th e s u p e r io r th y r o id a r te r y ) . T h e in te r n a l b r a n c h S L N d iv id e s in to a n
u p p e r b r a n c h a n d a lo w e r b r a n c h . T h e u p p e r b r a n c h s u p p lie s th e m u c o u s m e m -
b r a n e o f lo w e r p a r t o f p h a r y n x , e p ig lo ttis , v a lle c u la , a n d v e s tib u le o f th e la r y n x .
T h e lo w e r b r a n c h d e s c e n d s in th e m e d ia l w a ll o f th e p y r ifo r m fo ssa b e n e a th th e
m u c o u s m e m b r a n e . I t s u p p lie s th e a r y e p ig lo ttic fo ld a n d th e m u c o u s m e m b r a n e
o f th e la r y n x u p to th e le v e l o f th e v o c a l fo ld s . T h e in te r n a l b r a n c h S L N p r o v id e s
g e n e r a l s e n s a tio n , in c lu d in g p a in , to u c h , a n d te m p e r a tu r e fo r th e tis s u e s u p e r io r
R. Arrangoiz et al.
to th e v o c a l fo ld s . T h e in te r n a l b r a n c h S L N is v u ln e r a b le d u r in g s u r g ic a l in te r -
v e n tio n s o f th e a n te r io r c e r v ic a l r e g io n , in c lu d in g c a r o tid e n d a r te r e c to m y a n d
c e r v ic a l s p in e s u r g e r y , w ith a n a n te r io r o r a n te r o la te r a l a p p r o a c h [ 5 1 ] . S in c e th e
n e r v e p a s s e s b e n e a th th e m u c o u s m e m b r a n e o f th e m e d ia l w a ll o f th e p ir ifo r m
fo s s a , it is a c c e s s ib le fo r in je c tio n o f lo c a l a n e s th e s ia , th u s p r o v id in g e x c e lle n t
a n e s th e s ia fo r m o s t o f th e p ir ifo r m fo s s a [ 5 2 ] .
T h e s m a lle r e x te r n a l b r a n c h o f S L N d e s c e n d s to th e r e g io n o f th e s u p e r io r
p o le o f th e th y r o id g la n d a n d c o u r s e s m e d ia lly a lo n g th e in fe r io r p h a r y n g e a l
c o n s tr ic to r m u s c le , p a s s in g u n d e r th e s te r n o th y r o id m u s c le , a lo n g s id e th e s u p e -
r io r th y r o id v e in a n d a r te r y ( p a s s e s p o s te r io r a n d m e d ia l to th e v e s s e ls ) [ 8 ] . T h e
e x te r n a l b r a n c h o f S L N s u p p lie s th e c r ic o th y r o id m u s c le , w h ic h is th e o n ly te n -
s o r m u s c le o f th e v o c a l c o r d s [ 3 7 ] . I n a d d itio n to its c o n tr ib u tio n to p h o n a tio n ,
th e c r ic o th y r o id m u s c le p la y s a r o le in th e o v e r a ll r e g u la tio n o f b r e a th in g b y its
c o n tr o l o f e x p ir a to r y r e s is ta n c e a n d flo w [ 5 3 ] . T h e n e r v e e n te r s th e c r ic o th y r o id
m u s c le la te r a lly o n its d e e p s u r fa c e . T h e e x te r n a l b r a n c h o f S L N a ls o c o n tr ib u te s
in n e r v a tio n s to th e p h a r y n g e a l p le x u s , w h ic h in n e r v a te s th e p a la te a n d p h a r y n x ,
a n d is fo r m e d b y th e e x te r n a l b r a n c h o f S L N , p h a r y n g e a l n e r v e s , b r a n c h e s fr o m
th e c r a n ia l n e r v e I X , a n d th e s y m p a th e tic tr u n k [ 1 8 ] [ 1 9 ] .
I n r o u g h ly 2 0 % o f in d iv id u a ls , th e e x te r n a l b r a n c h o f th e S L N is u n d e r th e in -
fe r io r p h a r y n g e a l c o n s tr ic to r m u s c le a n d c a n n o t b e v is u a liz e d , b u t it c a n b e s ti-
m u la te d u s in g a n e r v e p r o b e [ 1 0 ] . T h e e x te r n a l b r a n c h o f th e S L N is c lo s e ly r e -
la te d w ith th e s u p e r io r th y r o id v a s c u la r p e d ic le a t th e c a p s u le o f th e s u p e r io r
p o le o f th e th y r o id [ 1 0 ] [ 1 2 ] . D u e to th e c lo s e a n a to m ic a l r e la tio n s h ip , th e e x -
te r n a l b r a n c h o f th e S L N is a t r is k o f in ju r y d u r in g th y r o id s u r g e r ie s . N u m e r o u s
a n a to m ic a l v a r ia tio n s e x is t b e tw e e n th e c o u r s e o f th e e x te r n a l b r a n c h o f th e S L N ,
th e s u p e r io r th y r o id a r te r y , a n d th e s u p e r io r p o le o f th e th y r o id [ 8 ] [ 5 4 ] . C e r n e a
e t a l. [ 5 4 ] [ 5 5 ] d e p ic te d th e le v e l a t w h ic h th e e x te r n a l b r a n c h o f th e S L N c r o s s e s
b e h in d th e s u p e r io r th y r o id a l a r te r y ( T a b le 2 ) .
5. Thyroid Gland Physiology

I o d in e M e ta b o lis m
I o d in e is a v ita l m ic r o n u tr ie n t th a t c a n b e o b ta in e d o n ly v ia d ie ta r y s o u r c e s
[ 5 6 ] [ 5 7 ] . I t c ir c u la te s in th e b lo o d s tr e a m in its io n iz e d fo r m , io d id e ( I− ) a n d is a
k e y in g r e d ie n t fo r th y r o id h o r m o n e s y n th e s is , a c c o u n tin g fo r 6 5 % o f th e m o le -
c u la r w e ig h t o f T 4 ( th y r o x in e ) a n d 5 9 % o f T 3 ( tr iio d o th y r o n in e ) [ 5 6 ] . In o r d e r
T a b le 2 . C la s s ific a tio n o f th e e x te r n a l b r a n c h o f th e s u p e r io r la r y n g e a l n e r v e ( S L N ) [ 5 4 ] .
C la s s ific a tio n o f th e E x te r n a l B r a n c h o f th e S L N [5 4 ].
T y p e 1 : E x te r n a l b r a n c h o f th e S L N c r o s s e s th e s u p e r io r th y r o id v e s s e ls 1 c m o r m o re a b o v e a
h o r iz o n ta l p la n e p a s s in g th r o u g h th e u p p e r b o r d e r o f s u p e r io r th y r o id p o le .
T y p e 2 a : T h e n e r v e c r o s s e s t h e v e s s e ls le s s t h a n 1 c m a b o v e th e p la n e .
T y p e 2 b : T h e n e r v e c r o s s e s th e v e s s e ls b e lo w th e p la n e .
• C e r n e a ty p e 2 b is th e m o s t c o m m o n p o s itio n .
• C e r n e a ty p e 2 b n e r v e s a r e a ls o th e m o s t v u ln e r a b le to in ju r y d u r in g th y r o id e c to m y [ 5 5 ] .
R. Arrangoiz et al.
to p r o v id e th e a d u lt th y r o id g la n d w ith th e 6 0 μ g o f I − p e r d a y r e q u ir e d to s y n -
th e s iz e n o r m a l a m o u n ts o f th y r o id h o r m o n e , th e r e c o m m e n d e d d a ily in ta k e o f
io d in e is r o u g h ly 1 5 0 m ic r o g r a m s [ 5 8 ] , w h ic h c a n b e o b ta in e d fr o m fo o d s su c h
a s fis h , m ilk , e g g s , o r a s a d d itiv e s in b r e a d o r s a lt [ 5 7 ] [ 5 9 ] . U n d e r n o r m a l p h y s i-
o lo g ic c o n d itio n s , th e th y r o id g la n d c o n ta in s m o r e th a n 9 0 % o f th e to ta l b o d y
I− , w ith a n I− c o n c e n tr a tio n 2 0 to 4 0 tim e s h ig h e r th a n th a t o f th e s e r u m [6 0 ].
In th e p r o x im a l g a s tr o in te s tin a l tr a c t ( s to m a c h a n d je ju n u m ) , io d in e is
p r o m p tly c o n v e r te d to its io n iz e d fo r m , io d id e ( I− ) , a n d a b so rb e d in to th e
b lo o d s tr e a m , a n d fr o m th e r e it is d is tr ib u te d u n ifo r m ly th r o u g h o u t th e e x tr a c e l-
lu la r c o m p a r tm e n t. I − is a c tiv e ly tr a n s p o r te d in to th e th y r o id fo llic u la r c e lls b y
a n a d e n o s in e tr ip h o s p h a te ( A T P ) d e p e n d e n t p r o c e s s [ 6 1 ] . T h e N a + / I− s y m p o r -
te r ( N I S ) lo c a te d o n th e b a s o la te r a l p la s m a m e m b r a n e o f th e th y r o id fo llic u la r
c e lls ( w h ic h c o n ta in 1 3 tr a n s m e m b r a n e s e g m e n ts ) is r e s p o n s ib le fo r th e a c tiv e
tra n sp o r t m e c h a n is m [ 6 0 ] [ 6 2 ] . I t e x p lo its th e in w a r d ly d ir e c te d N a + g r a -
d ie n t g e n e r a te d b y th e N a + /K + A T P a s e to c o u p le m o v e m e n t o f N a + a n d I−
fr o m th e b lo o d in to th e th y r o id fo llic u la r c e ll c y to p la s m [6 0 ]. T w o N a + io n s
e n te r fo r e v e r y I − , a n d th is 2 :1 s to ic h io m e tr y g e n e r a te s a p o s itiv e ly c h a r g e d
in w a r d c u r r e n t [ 5 6 ] [ 6 2 ] . T h e a c tiv ity o f th e N IS a n d u p ta k e o f I− a r e r e g u -
la te d b y th y r o id - s tim u la tin g h o r m o n e ( T S H ) a n d b y I − its e lf [ 6 2 ] . A s m e n -
tio n e d p r e v io u s ly th e th y r o id g la n d s to r e s m o r e th a n 9 0 % o f th e b o d y ´s I− c o n -
te n t a n d a c c o u n ts fo r o n ly o n e th ir d o f th e p la s m a I − lo s s [ 6 0 ] . T h e r e m a in in g
p la s m a I − is c le a r e d v ia r e n a l e x c r e tio n , a p p r o x im a te ly 9 0 % o f in g e s te d io d in e is
e x c r e te d in th e u r in e [ 5 6 ] [ 6 3 ] [ 6 4 ] .
A s s o o n a s th e I − m o le c u le e n te r s th e th y r o id fo llic u la r c e ll, a n e le c tr o c h e m i-
c a l g r a d ie n t p r o p e ls th e I − m o le c u le to th e a p ic a l s u r fa c e o f th e th y r o id fo llic u la r
c e ll. T h e m e c h a n is m o f th e e fflu x o f I − fr o m th e c e ll c y to p la s m in to th e th y r o id
fo llic u la r lu m e n is le s s w e ll c h a r a c te r iz e d . A tr a n s m e m b r a n e p r o te in , P e n d r in , is
b e lie v e d to p la y a r o le in th e a p ic a l I − tr a n s p o r t [ 5 6 ] [ 6 0 ] [ 6 2 ] [ 6 5 ] , w h ic h is
m u t a t e d in P e n d r e d ’s s y n d r o m e , le a d in g t o a p a r t ia l d e f e c t in t h e o r g a n if ic a t io n
o f io d id e . P e n d r e d ’s s y n d r o m e is c h a r a c te r iz e d b y h e r e d ita r y s e n s o r in e u r a l
d e a fn e s s a n d r a r e ly e u th y r o id g o ite r [ 5 6 ] [ 6 0 ] [ 6 2 ] [ 6 5 ] .
T h y r o g lo b u lin
T h y r o g lo b u lin is th e m o s t h ig h ly e x p r e s s e d p r o te in in th e th y r o id g la n d a n d it
is s y n th e s iz e d b y th e th y r o id fo llic u la r c e lls [ 6 6 ] . T h y r o g lo b u lin it is o n e o f th e
la r g e s t p r o te in s in th e h u m a n b o d y , h a v in g a m o le c u la r w e ig h t o f 6 6 0 k D a , a n d
c o n s is tin g o f a s ig n a l p e p tid e s e q u e n c e o f a p p r o x im a te ly 2 7 5 0 a m in o a c id r e s i-
d u e s [ 6 6 ] [ 6 7 ] . It h a s a h o m o g e n e o u s s tr u c tu r e c o n s is tin g o f fo u r d is tin c t r e -
g io n s : th r e e c y s te in e - r ic h r e p e titiv e d o m a in s ( T g 1 , T g 2 , a n d T g 3 ) a n d th e c h o li-
n e s te r a s e - lik e ( C h E L ) d o m a in ( C - te r m in u s o f th e m o le c u le ) , w h ic h is h ig h ly
h o m o lo g o u s to a c e ty lc h o lin e [ 6 6 ] [ 6 8 ] .
T h e s y n th e s is o f th y r o g lo b u lin is r e g u la te d b y T S H a n d b y v a r io u s tr a n s c r ip -
tio n fa c to r s , in c lu d in g th y r o id tr a n s c r ip tio n fa c to r 1 ( T T F 1 ) , T T F 2 , a n d p a ir e d
b o x g e n e 8 ( P a x 8 ) [ 6 6 ] . T h y r o g lo b u lin m o le c u le s u n d e r g o o x id a tio n ( p a r t o f th e
R. Arrangoiz et al.
fo ld in g p r o c e s s ) , g ly c o s y la tio n a n d d im e r iz a tio n [ 6 6 ] [ 6 8 ] . S e v e r a l m o le c u la r
c h a p e r o n e s , in c lu d in g B iP , G R P 9 4 , E R p 2 9 , G R P 1 7 0 , E R p 7 2 , a n d c a ln e x in , a r e
in v o lv e d in th e m a tu r a tio n o f th y r o g lo b u lin a n d a c t a s in tr a c e llu la r q u a lity c o n -
tr o l to e n s u r e th a t o n ly p r o p e r ly fo ld e d a n d g ly c o s y la te d th y r o g lo b u lin m o le -
c u le s a r e u ltim a te ly r e le a s e d [ 5 7 ] [ 6 6 ] [ 6 7 ] . T h e p r o c e s s is s o m e w h a t p r o tr a c te d ,
w ith a h a lf life o f 9 0 m in u te s to 1 2 0 m in u te s fo r n e w ly s y n th e s iz e d th y r o g lo b u lin
to a r r iv e a t th e G o lg i c o m p le x [ 6 9 ] . I n th e G o lg i a p p a r a tu s it is in c o r p o r a te d in to
e x o c y tic v e s ic le s th a t m ig r a te to th e a p ic a l m e m b r a n e o f th e fo llic u la r c e ll, w h e r e
th e o r g a n ific a tio n a n d c o u p lin g p r o c e s s ta k e s p la c e [ 5 7 ] [ 6 6 ] .
O r g a n ific a tio n a n d C o u p lin g
E v e n th o u g h o r g a n ific a tio n a n d c o u p lin g a r e o fte n d is c u s s e d a s d is c r e te s te p s ,
b o th r e a c tio n s a r e c a ta ly z e d b y th y r o id p e r o x id a s e ( T P O ) a n d o c c u r c o n c u r r e n t-
ly [ 6 0 ] . T h e p r o c e s s b y w h ic h o x id iz e d io d id e a tta c h e s to ty r o s y l r e s id u e s o n th e
th y r o g lo b u lin m o le c u le is r e fe r r e d to a s o r g a n ific a tio n . T h e s e p r o c e s s le a d s to
th e fo r m a tio n o f m o n o io d o ty r o s in e ( M I T ) o r d iio d o ty r o s in e ( D I T ) r e s id u e s , s till
lo c a te d w ith in th e th y r o g lo b u lin m o le c u le [ 5 7 ] [ 6 0 ] . O f th e 1 3 2 to 1 4 0 ty r o s y l r e -
s id u e s in e a c h m o le c u le o f d im e r iz e d h u m a n th y r o g lo b u lin ( th e r e p o r te d n u m -
b e r d iffe r s b e c a u s e o f m o d ific a tio n s in c o m p le m e n ta r y D N A ( c D N A ) s e q u e n c -
in g ) , o n ly a s m a ll s u b s e t, a r e tr u ly s u s c e p tib le to io d in a tio n [ 5 7 ] [ 6 0 ] [ 6 8 ] [ 7 0 ] .
A lth o u g h e a c h m o le c u le o f m a tu r e th y r o g lo b u lin c o n ta in s fiv e to 5 0 io d in e
a to m s , o n ly s o m e io d in a te d s ite s a r e u ltim a te ly in v o lv e d in h o r m o n o g e n e s is b e -
c a u s e o f th e ir s p a tia l o r ie n ta tio n [ 5 7 ] [ 6 0 ] .
A fte r th e fo r m a tio n o f M I T a n d D I T r e s id u e s , th e c o u p lin g r e a c tio n tr a n s -
p ir e s : tw o D IT r e s id u e s c o m b in e to fo r m T 4 ( te tr a io d o th y r o n in e ) o r o n e M IT
c o m b in e s w ith o n e D I T to c r e a te T 3 ( tr iio d o th y r o n in e ) [ 5 7 ] [ 6 0 ] . F ig u r e 1 1
s h o w s th e m o le c u la r s tr u c tu r e s o f T 4 a n d T 3 . I n th is r e a c tio n , a ls o c a ta ly z e d b y
T P O a n d m e d ia te d b y h y d r o g e n p e r o x id e ( H 2O 2) , th e io d in a te d p h e n y l g r o u p o f
a ty r o s y l r e s id u e is d o n a te d to b e c o m e th e o u te r r in g o f th e io d o th y r o n in e a c -
c e p to r s ite [ 6 0 ] . T y r o s in e s 5 , 2 5 5 4 , a n d 2 7 4 7 a r e th e m o s t im p o r ta n t a c c e p to r
s ite s , w h ile ty r o s in e s 1 3 0 , 8 4 7 , a n d 1 4 4 8 a r e th e d o m in a n t d o n o r s [ 6 0 ] [ 7 0 ] .
R o u g h ly o n e th ir d o f T 4 is fo r m e d b y th e a c c e p to r – d o n o r p a ir o f ty r o s in e 5 a n d
ty r o s in e 1 3 0 [ 5 7 ] . A fte r th e c o u p lin g r e a c tio n , th e n e w ly fo r m e d T 3 a n d T 4 a r e
s till in c o r p o r a te d w ith in th e th y r o g lo b u lin m o le c u le [ 5 7 ] . U n d e r n o r m a l c ir -
c u m s ta n c e s ( n o r m a l io d in e s u p p ly a n d n o r m a l th y r o id fu n c tio n ) , th e ty p ic a l
th y r o g lo b u lin m o le c u le c o n ta in s 2 .5 r e s id u e s o f T 4 , 0 .7 o f T 3 , 4 .5 o f D I T , a n d 5
o f M IT [5 7 ].
S e c r e tio n a n d S to r a g e
A s s o o n a s o r g a n ific a tio n a n d c o u p lin g a r e c o m p le te , th e io d in a te d , m a tu r e
th y r o g lo b u lin is r e le a s e d in to th e fo llic u la r lu m e n , w h e r e it m a k e s u p m o r e th a n
9 5 % o f th e c o llo id [ 5 7 ] [ 7 1 ] . R o u g h ly tw o th ir d s o f th e th y r o g lo b u lin fo u n d in
th e c o llo id is in th e s o lu b le 6 6 0 k D a d im e r iz e d fo r m , b u t fr e e m o n o m e r s a n d te -
tr a m e r s a r e a ls o fo u n d in m in im a l a m o u n ts [ 5 7 ] [ 7 1 ] . T h e a d d itio n a l 3 4 % o f th e
th y r o g lo b u lin m o le c u le s e x is ts in a d e n s e , h ig h ly c o n c e n tr a te d in s o lu b le fo r m
( i T g ) , w ith h ig h io d in e c o n te n t b u t w ith v ir tu a lly u n d e te c ta b le th y r o id h o r m o n e \
R. Arrangoiz et al.
F ig u r e 1 1 . M o le c u la r s tr u c tu r e o f T 4 a n d T 3 a n d th y r o id h o r m o n e s y n th e s is .
r e s id u e s [ 5 7 ] [ 6 4 ] [ 7 1 ] . W h e n th e th y r o id fo llic u la r c e lls a r e s tim u la te d b y th y -

r o id s tim u la tin g h o r m o n e ( T S H ) , th y r o g lo b u lin is m o b iliz e d fr o m th e c o llo id
a n d r e tu r n s to th e th y r o c y te v ia a p r o c e s s c a lle d m ic r o p in o c y to s is . B e c a u s e o f
th e ir p h y s ic a l ju x ta p o s itio n to th e a p ic a l m e m b r a n e a n d s o lu b ility , n e w ly s e -
c r e te d th y r o g lo b u lin m o le c u le s a r e ta k e n u p fir s t [ 6 4 ] [ 7 1 ] [ 7 2 ] . P its c o a te d b y
c la th r in a r e fo r m e d o n th e lu m in a l s id e o f th e a p ic a l m e m b r a n e o f th e th y r o c y te s
a n d h e lp in te r n a liz e th e th y r o g lo b u lin m o le c u le . T h e p its th e n in v a g in a te to
R. Arrangoiz et al.
fo rm in tr a c e llu la r v e s ic le s , w h ic h s h e d th e ir c la th r in c o a ts a n d q u ic k ly fu s e w ith
e a r ly e n d o s o m e s [ 5 7 ] [ 7 1 ] [ 7 3 ] . T h is c o m p le x p r o c e s s is th o u g h t to tr a n s p ir e v ia
a c o m b in a tio n o f n o n s p e c ific flu id p h a s e u p ta k e ( lik e ly th e m a in r o u te o f th y -
r o g lo b u lin u p ta k e le a d in g to d e g r a d a tio n a n d r e le a s e o f th y r o id h o r m o n e s ) a n d
r e c e p to r m e d ia te d u p ta k e ( w h ic h a p p e a r s to le a d to o th e r p o s t e n d o c y tic p a th -
w a y s) [5 7 ] [7 1 ] [7 4 ].
T h e in tr a c e llu la r th y r o g lo b u lin m o le c u le s fo llo w o n e o f a t le a s t th r e e d iffe r e n t
p a th w a y s : p r o te o ly tic d e s tr u c tio n in to its c o m p o n e n t p a r ts , r e c y c lin g b a c k to th e
fo llic u la r lu m e n , o r tr a n s c y to s is [ 5 7 ] [ 7 1 ] [ 7 4 ] . I n th e fir s t p a th w a y , th y r o g lo b u -
lin tr a v e ls th r o u g h th e e n d o s o m a l s y s te m to ly s o s o m e s , w h e r e M I T , D I T , T 4 ,
a n d T 3 r e s id u e s a r e s e le c tiv e ly r e m o v e d fr o m th e m o le c u le [ 5 7 ] [ 7 5 ] . T h e fr e e
M I T a n d D I T r e s id u e s r e le a s e d fr o m ly s o s o m e s c a n n o t m e r g e to s y n th e s iz e
T $ o r T 3 ; r a th e r , th e y a r e d e io d in a te d to p r o d u c e io d id e ( I − ) a n d ty r o s in e , b o th
o f w h ic h a r e th e n r e u s e d fo r n o v e l th y r o g lo b u lin s y n th e s is a n d o r g a n ific a tio n .
T h e c h ie f e n z y m e r e s p o n s ib le fo r th is io d id e r e c y c lin g p r o c e s s is io d o ty r o s in e
d e h a lo g e n a s e 1 ( D E H A L 1 ) , a n N A D P H d e p e n d e n t tr a n s m e m b r a n e p r o te in lo -
c a te d a t th e a p ic a l m e m b r a n e o f fo llic u la r c e lls [ 7 6 ] [ 7 7 ] . L a s tly , c a th e p s in s D , B ,
a n d L , w h ic h a r e ly s o s o m a l p r o te a s e s , a c t a t s p e c ific c le a v a g e s ite s o n th y r o g lo -
b u lin to p r o d u c e h o r m o n e e n r ic h e d p o ly p e p tid e s . T h e s e a r e th e n fu r th e r h y d r o -
ly z e d b y e x o p e p tid a s e s ( ly s o s o m a l d ip e p tid a s e I ) to r e le a s e fr e e th y r o id h o r -
m o n e s in to th e c y to p la s m [ 7 8 ] [ 7 9 ] .
T r a d itio n a lly , th e s e c r e tio n o f th y r o id h o r m o n e s in to th e b lo o d s tr e a m h a s
b e e n c r e d ite d to p a s s iv e d iffu s io n , b u t m o r e r e c e n t e v id e n c e c o r r o b o r a te s a
tr a n s p o r t s y s te m lo c a te d a t th e fo llic u la r th y r o id c e ll b a s o la te r a l m e m b r a n e .
T r a n s m e m b r a n e th y r o id h o r m o n e s tr a n s p o r te r s , p a r tic u la r ly m o n o c a r b o x y la te
tr a n s p o r te r 8 ( M C T 8 ) a n d O A T P 1 C 1 ( a m e m b e r o f th e s o d iu m in d e p e n d e n t
o r g a n ic a n io n tr a n s p o r tin g p o ly p e p tid e fa m ily ) , h a v e b e e n w e ll d e s c r ib e d in p e -
r ip h e r a l tis s u e . T h e la te s t s tu d ie s h a v e d e m o n s tr a te d im m u n o h is to c h e m ic a l lo -
c a liz a tio n o f M C T 8 to th e b a s o la te r a l m e m b r a n e o f th e th y r o c y te a n d h a v e a ls o
s u g g e s te d th a t M C T 8 is in fa c t n e c e s s a r y fo r n o r m a l th y r o id h o r m o n e s e c r e tio n
fr o m th e th y r o id g la n d [ 8 0 ] [ 8 1 ] . F ig u r e 1 1 s u m m a r iz e s th y r o id h o r m o n e s y n -
th e s is a n d s e c r e tio n .
T h y r o id H o r m o n e T r a n s p o r t
U n d e r n o r m a l c o n d itio n s , 9 0 % o f th e h o r m o n e s e c r e te d b y th e th y r o id g la n d
is in th e fo r m o f T 4 a n d th e o th e r 1 0 % is T 3 [ 8 2 ] . M o s t o f th e th y r o id h o r m o n e
c ir c u la te s b o u n d to s e r u m p r o te in s , o n ly 0 .3 % o f T 3 a n d 0 .0 3 % o f T 4 a r e fr e e in
s o lu tio n [ 8 3 ] [ 8 4 ] . T h is is r e fle c te d in th e h a lf- liv e s o f th e h o r m o n e s : T 3 h a s a
h a lv e life o f a b o u t 2 4 h o u r s , a n d T 4 h a s a h a lv e life o f a b o u t 6 to 7 d a y s [ 8 4 ] . T h e
m a jo r ity o f th e th y r o id h o r m o n e c ir c u la te s b o u n d to c a r r ie r p r o te in s , w ith 9 5 %
b o u n d to e ith e r th y r o id b in d in g g lo b u lin ( T B G ) , tr a n s th y r e tin ( T T R ) , o r a lb u -
m in . T B G h a s th e h ig h e s t a ffin ity fo r th y r o id h o r m o n e a n d is in d u c e d b y e s tr o -
g e n a n d th y r o id h o r m o n e . T h e r e m a in in g 4 % to 5 % is b o u n d to o th e r m in o r
th y r o id h o r m o n e c a r r ie r s , s u c h a s lip o p r o te in s , im m u n o g lo b u lin s , a n d lip o c a lin s
[8 4 ] [8 5 ]. T r a n sth y r e tin ( fo r m e r ly c a lle d th y r o x in e b in d in g p r e - a lb u m in o r
R. Arrangoiz et al.
T B P A ) is p r e s e n t in b o th s e r u m a n d c e r e b r o s p in a l flu id a n d h a s a s o m e w h a t
lo w e r a ffin ity th a n T B G ; s e r u m a lb u m in h a s a r a th e r lo w a ffin ity fo r th y r o id
h o r m o n e b u t is p r e s e n t is la r g e a m o u n ts in s e r u m [ 8 4 ] [ 8 5 ] . T h e c a r r ie r p r o te in s
s e r v e b o th a s a s ta b le r e s e r v o ir o f e x tr a th y r o id a l th y r o id h o r m o n e s a n d a s a s a fe
g u a r d fo r th e v e r y h y d r o p h o b ic fr e e h o r m o n e fr o m its a q u e o u s e n v ir o n m e n t
[ 8 2 ] [ 8 4 ] [ 8 5 ] . A s a c o n s e q u e n c e o f th is m e th o d o f d is tr ib u tio n a n d b u ffe r in g , T 4
h a s lo n g e s t h a lv e life o f a n y h o r m o n e ( 6 to 7 d a y s ) , a n d its s e r u m c o n c e n tr a tio n
o f 0 .1 μ M is s e c o n d o n ly to c o r tis o l [ 8 5 ] .
T h e s y n th e s is a n d r e le a s e o f T B G a r e a ffe c te d b y s e v e r a l h o r m o n e s : g lu c o c o r -
tic o id s a n d a n d r o g e n s r e d u c e th e a m o u n t o f T B G , w h ile e s tr o g e n s in c r e a s e T B G
le v e ls , e s p e c ia lly d u r in g p r e g n a n c y [ 8 3 ] [ 8 5 ] . T h e s e o b s e r v a tio n s a r e o f s o m e
c lin ic a l r e le v a n c e fo r in d iv id u a ls b e in g tr e a te d w ith th y r o id h o r m o n e s in c e th e
le v e ls o f e x o g e n o u s th y r o id h o r m o n e r e q u ir e d w ill b e a ffe c te d b y th e p r e s e n c e o f
o th e r h o r m o n e s . A s a n e x a m p le , p a tie n ts w ith G r a v e s ’ d is e a s e m a y h a v e th e ir
d is o r d e r e x a c e r b a te d b y c o n c u r r e n t a n d r o g e n t h e r a p y ( e .g ., fo r m e ta s ta tic b r e a s t
c a n c e r).
M e c h a n is m o f T h y r o id H o r m o n e A c tio n
C ir c u la tin g fr e e T 4 a n d T 3 c a n b e ta k e n u p b y p e r ip h e r a l c e lls a t a n y tim e , a n d
b o th T 4 a n d T 3 c a n s w iftly d e ta c h fr o m th e ir c a r r ie r p r o te in s to in c r e a s e th e
a v a ila b ility o f fr e e h o r m o n e w h e n n e c e s s a r y [ 8 2 ] [ 8 5 ] . T h e e n tr y o f fr e e T 4 o r T 3
in to ta r g e t c e lls is m e d ia te d b y a v a r ie ty o f p la s m a m e m b r a n e tr a n s p o r te r s , in -
c lu d in g th e a fo r e s a id m o n o c a r b o x y la te tr a n s p o r te r s ( in c lu d in g M C T 8 a n d M C T
1 0 ) a n d O A T P 1 C 1 , a s w e ll a s th e N a + ta u r o c h o la te c o - tr a n s p o r tin g p o ly p e p tid e ,
th e L ty p e a m in o a c id tr a n s p o r te r s ( L A T 1 a n d L A T 2 ) , a n d fa tty a c id tr a n s lo c a s e
[8 0 ] [8 1 ]. T h o u g h th e M C T tr a n s p o r te r s a r e w id e ly e x p r e s s e d in m o s t tis s u e s ,
O A T P 1 C 1 is m u c h m o r e s p e c ific , e x p r e s s e d p r e d o m in a n tly in th e b r a in a n d
te s te s [ 8 1 ] . T h e tr a n s p o r te r s a ls o v a r y in th e ir lig a n d s p e c ific ity , w ith M C T 1 0
d e m o n s tr a tin g in c r e a s e d a ffin ity fo r T 3 a n d O A T P 1 C 1 d e m o n s tr a tin g s tr o n g
p re fe re n c e fo r T 4 [8 1 ] [8 6 ].
A ll k n o w n a c tio n s o f th y r o id h o r m o n e s a p p e a r to b e m e d ia te d b y th e th y r o id
h o r m o n e r e c e p to r , w h ic h is a m e m b e r o f th e s te r o id h o r m o n e r e c e p to r s u p e r fa -
m ily . T 3 a n d T 4 e n te r c e lls b y p a s s iv e d iffu s io n a n d b in d a c y to p la s m ic b in d in g
p r o te in . O n c e in s id e th e c e ll, T 4 is d e io d in a te d b y th e io d o th y r o n in e d e io d in a s e
fa m ily o f s e le n o p r o te in s ( T y p e 1 , 2 , 3 d e io d in a s e ) to T 3 , w h ic h m o v e s to th e
n u c le u s ( e ith e r fa c ilita te d b y th e b in d in g p r o te in o r b y d iffu s io n ) a n d b in d s to
t h e t h y r o i d h o r m o n e r e c e p t o r [ 1 2 ] [ 8 2 ] . T h e o u t e r ( 5 ') - r i n g d e i o d i n a t i o n o f t h e
p r o h o r m o n e T 4 p r o d u c e s th e a c tiv e fo r m o f T 3 , w h ile in n e r ( 5 ) r in g d e io d in a -
tio n p r o d u c e s th e in a c tiv e m e ta b o lite ( r e v e r s e T 3 ; r T 3 ) [ 8 7 ] [ 8 8 ] . I n g e n e r a l, th e
th y r o id h o r m o n e r e c e p to r s a r e c o n s titu tiv e ly a c tiv e a s r e p r e s s o r s in th e a b s e n c e o f
h o r m o n e , a lth o u g h r e p r e s s io n o f g e n e e x p r e s s io n c a n a ls o b e h o r m o n a lly r e g u -
la te d ( a s in th e c a s e o f th e α a n d β T S H s u b - u n it g e n e s ) [ 8 2 ] . T h e n o n - h o r m o n e
b in d in g th y r o id h o r m o n e r e c e p to r - α 2 is p r o b a b ly a c o n s titu tiv e r e p r e s s o r a n d
a p p a r e n tly a c ts a s a c o m p e titiv e in h ib ito r o f th e b in d in g o f o th e r th y r o id h o r -
R. Arrangoiz et al.
m o n e r e c e p to r is o fo r m s to D N A [ 8 2 ] .
T 3 c a n a c t w ith in th e n u c le u s , a t th e p la s m a m e m b r a n e , in th e c y to p la s m , a n d
a t th e m ito c h o n d r ia [ 8 9 ] . G e n o m ic a c tio n , w h ic h is d e fin e d a s th e a c tio n o f th e
th y r o id h o r m o n e s in th e n u c le i, in v o lv e s th e b in d in g o f T 3 to th y r o id h o r m o n e
n u c le a r r e c e p to r s ( T R ) , w h ic h th e n fu n c tio n a s T 3 in d u c ib le tr a n s c r ip tio n fa c -
to r s th a t u p r e g u la te th e e x p r e s s io n o f th y r o id h o r m o n e r e s p o n s iv e g e n e s [ 8 2 ]
[ 8 9 ] [ 9 0 ] . T w o m a jo r s u b ty p e s o f T R h a v e b e e n id e n tifie d , e a c h o f w h ic h h a s
se v e r a l iso fo r m s. L o c a te d o n c h ro m o so m e 1 7 , th e T R α g e n e e n c o d e s T R α 1 ,
w h ic h b in d s T 3 , a s w e ll a s tw o o th e r n o n - T 3 - b in d in g p r o d u c ts : T R α 2 a n d T R α 3
[8 9 ] [9 0 ]. T R α 1 is c o n s titu tiv e ly e x p re sse d d u r in g e m b r y o n ic d e v e lo p m e n t,
w h ile in p o s tn a ta l life , it is p r e d o m in a n tly e x p r e s s e d in b r a in , h e a r t, b o n e , a n d
s k e le ta l m u s c le [ 8 9 ] [ 9 0 ] . T h e r e a r e th r e e T 3 - b in d in g T R β is o fo r m s e n c o d e d b y
th e T R β g e n e o n c h r o m o s o m e 3 : T R β 1 is e x p r e s s e d w id e ly , T R β 2 p r e d o m in a n tly
e x p r e s s e d in b r a in , r e tin a , a n d in n e r e a r , a n d T R β 3 in k id n e y , liv e r , a n d lu n g
[ 8 9 ] [ 9 0 ] . T h e p h e n o ty p ic s ig n ific a n c e o f th is tis s u e s p e c ific T R e x p r e s s io n is
s till u n d e r in v e s tig a tio n .
R e g u la tio n o f T h y r o id H o r m o n e
T h e tr a d itio n a l c o m p r e h e n s io n o f th y r o id h o r m o n e h e m o s ta s is is fo u n d e d o n
th e n e g a tiv e fe e d b a c k s y ste m o f th e h y p o th a la m ic p itu ita r y th y r o id a x is ( H P T
a x is s e e F ig u r e 1 2 ) [ 9 0 ] [ 9 1 ] [ 9 2 ] [ 9 3 ] . T h y r o tr o p in r e le a s in g h o r m o n e ( T R H )
n e u r o n s lo c a te d in th e p a r a v e n tr ic u la r n u c le u s o f th e h y p o th a la m u s ( P V H )
s e n s e th e c ir c u la tin g le v e ls o f th y r o id h o r m o n e s ( T 4 a n d T 3 ) . W h ile o th e r r e -
g io n s o f th e h y p o th a la m u s , in c lu d in g th e la te r a l a n d v e n tr o m e d ia l n u c le i, a ls o
e x p r e s s T R H , o n ly th e P V H is tig h tly r e g u la te d b y th y r o id h o r m o n e s ( T 4 a n d
T 3 ) [ 9 1 ] . T h y r o id h o r m o n e s b in d to th e T R β 2 is o fo r m in th e P V H a n d in d u c e
T R H g e n e e x p r e s s io n v ia a n e g a tiv e fe e d b a c k fa s h io n [ 9 1 ] . W h e n T 4 a n d T 3 le -
v e ls a r e h ig h , T R H e x p r e s s io n is lo w a n d v ic e v e r s a [ 9 1 ] [ 9 3 ] . T h e p itu ita r y p o r -
ta l sy ste m th e n d e liv e r s T R H to th e a n te r io r p itu ita r y g la n d , w h e r e T S H ( a ls o
F ig u r e 1 2 . H y p o th a la m ic p itu ita r y th y r o id a x is .
R. Arrangoiz et al.
c a lle d th y r o tr o p in o r th y r o id s tim u la tin g h o r m o n e ) is s y n th e s iz e d a n d s e c r e te d .

T h y r o id h o r m o n e s ( T 4 a n d T 3 ) w ie ld a n e g a tiv e fe e d b a c k e ffe c t o n th is s te p a s
w e ll. O n c e it is r e le a s e d fr o m th e a n te r io r p itu ita r y g la n d , T S H b in d s to T S H re -
c e p to r s ( T S H R ) o n th e b a s a l m e m b r a n e o f th e th y r o id fo llic u la r c e lls , w h ic h a c -
tiv a te s a n in tr a c e llu la r c a s c a d e , in c lu d in g th e a c tiv a tio n o f a d e n y la te c y c la s e [ 6 4 ]
[ 9 2 ] [ 9 3 ] . T h e s u b s e q u e n t in c r e a s e in c y c lic a d e n o s in e m o n o p h o s p h a te ( c A M P )
fu e ls n e a r ly e v e r y s te p in th y r o id h o r m o n e s y n th e s is , in c lu d in g io d in e u p ta k e ,
s y n th e s is o f th y r o g lo b u lin , o r g a n ific a tio n a n d c o u p lin g , a n d fo llic u la r c e ll u p ta k e
o f th y r o g lo b u lin fr o m th e c o llo id [ 9 3 ] .
A n a d d itio n a l k e y c o m p o n e n t o f th y r o id h o r m o n e c o n tr o l is th e a v a ila b ility o f
io d in e . A s fo r m e r ly d is c u s s e d , io d in e is c r u c ia l fo r th y r o id h o r m o n e s y n th e s is .
I o d in e d e fic ie n c y le a d s to in c r e a s e in T S H s e c r e tio n , w h ic h s tim u la te s fo llic u la r
g r o w th a n d g o ite r fo r m a tio n [ 9 4 ] . T h e c o n d u c t o f th e th y r o id g la n d u n d e r c o n -
d itio n s o f io d in e e x c e s s is a little m o r e c o m p le x . L a r g e a m o u n ts o f io d in e a r e
fo u n d in s o m e m e d ic a tio n s , to p ic a l a n ti s e p tic s , r a d io lo g y c o n tr a s t a g e n ts , a n d
fo o d p r e s e r v a tiv e s [ 6 3 ] [ 9 4 ] .
I o d in e e s s e n tia lly p r o d u c e s a n in tr a th y r o id a l n e g a tiv e fe e d b a c k s y s te m u n d e r
n o r m a l c ir c u m s ta n c e s . I o d in e e x c e s s in h ib its its o w n o r g a n ific a tio n , w h ic h p r e v e n ts
o v e r p r o d u c tio n o f th y r o id h o r m o n e s [ 5 9 ] [ 9 2 ] [ 9 4 ] . T h is is c a lle d W o lff- C h a ik o ff
p h e n o m e n o n [ 9 4 ] . T h e p h e n o m e n o n is th o u g h t to b e d u e to in h ib itio n o f T P O
b y in tr a th y r o id a l o r g a n ic io d o c o m p o u n d s , b u t r e d u c e d in tr a th y r o id a l d e io d i-
n a s e a c tiv ity a ls o s e e m s to p la y a r o le [ 5 9 ] [ 9 4 ] . T h e in h ib itio n o f th y r o id h o r -
m o n e s y n th e s is is tr a n s ie n t, la s tin g a n y w h e r e b e tw e e n 2 4 to 4 8 h o u r s , e v e n w ith
c o n tin u e d a d m in is tr a tio n o f e x c e s s io d in e [ 5 9 ] [ 6 3 ] [ 9 2 ] . W ith in 2 4 h o u r s a fte r
a n a c u te io d in e lo a d , th e r e is a d e c r e a s e d e x p r e s s io n o f th e N I S , e n s u in g a r e -
d u c e d th y r o id a l u p ta k e o f io d in e a n d r e s u m p tio n o f n o r m a l th y r o id h o r m o n e
s y n th e s is [ 5 9 ] [ 9 2 ] [ 9 4 ] . T h is , s o c a lle d , e s c a p e fr o m th e W o lff- C h a ik o ff e ffe c t
p r e v e n ts d e v e lo p m e n t o f io d in e in d u c e d h y p o th y r o id is m .
6. Conclusion
A c o m p le te u n d e rs ta n d in g o f th e th y r o id e m b r y o lo g y , a n a to m y , h is to lo g y , a n d
p h y s io lo g y is e s s e n tia l to th e m o d e r n h e a d a n d n e c k s u r g e o n /e n d o c r in e s u r g e -
o n /th y r o id su rg e o n a s th e y m a y im p a c t th e c o m p le te n e s s o f s u r g e r y a s w e ll a s
th e c o m p lic a tio n s o f su rg e ry .
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h ttp s :/ / d o i.o r g / 1 0 .1 0 9 7 / 0 0 0 0 5 5 3 7 - 2 0 0 3 0 4 0 0 0 - 0 0 0 0 4
[ 4 4 ] S te in b e r g , J .L ., e t a l. ( 1 9 8 6 ) A n a to m y o f th e R e c u r r e n t L a r y n g e a l N e r v e : A
R e - D e s c r ip tio n . T h e J o u r n a l o f L a r y n g o lo g y & O to lo g y , 1 0 0 , 9 1 9 - 9 2 7 .
h ttp s :/ / d o i.o r g / 1 0 .1 0 1 7 / S 0 0 2 2 2 1 5 1 0 0 1 0 0 3 2 5
[ 4 5 ] L a h e y , F .H . a n d H o o v e r , W .B . ( 1 9 3 8 ) I n ju r ie s to th e R e c u r r e n t L a r y n g e a l N e r v e in
T h y r o id O p e r a tio n s : T h e ir M a n a g e m e n t a n d A v o id a n c e . A n n a ls o f S u r g e r y , 1 0 8 ,
5 4 5 - 5 6 2 . h ttp s :/ / d o i.o r g / 1 0 .1 0 9 7 / 0 0 0 0 0 6 5 8 - 1 9 3 8 1 0 0 0 0 - 0 0 0 0 6
[ 4 6 ] A s g h a r p o u r , E ., e t a l. ( 2 0 1 2 ) R e c u r r e n t L a r y n g e a l N e r v e L a n d m a r k s R e v is ite d . H e a d
N e c k , 3 4 , 1 2 4 0 - 1 2 4 6 . h ttp s :/ / d o i.o r g / 1 0 .1 0 0 2 / h e d .2 1 8 8 2
[4 7 ] K a is h a , W ., W o b e n jo , A . a n d S a id i, H . (2 0 1 1 ) T o p o g r a p h y o f th e R e c u r r e n t L a r y n -
g e a l N e rv e in R e la tio n to th e T h y r o id A r te r y , Z u c k e r k a n d l T u b e r c le , a n d B e r r y L i-
g a m e n t in K e n y a n s . C lin ic a l A n a to m y , 2 4 , 8 5 3 -8 5 7 .
h ttp s :/ /d o i.o r g / 1 0 .1 0 0 2 / c a .2 1 1 9 2
[ 4 8 ] G u r le y ik , E . a n d G u r le y ik , G . ( 2 0 1 2 ) I n c id e n c e a n d S u r g ic a l I m p o r ta n c e o f Z u c k e r -
k a n d l’s T u b e r c le o f th e T h y r o id a n d I ts R e la tio n s w ith R e c u r r e n t L a r y n g e a l N e r v e .
I S R N S u r g e r y , 2 0 1 2 , A r tic le I D : 4 5 0 5 8 9 .
[ 4 9 ] D e d o , H .H . ( 1 9 7 0 ) T h e P a r a ly z e d L a r y n x : A n E le c tr o m y o g r a p h ic S tu d y in D o g s a n d
H u m a n s. L a ry n g o sc o p e , 8 0 , 1 4 5 5 -1 5 1 7 .
h ttp s :/ / d o i.o r g / 1 0 .1 2 8 8 / 0 0 0 0 5 5 3 7 - 1 9 7 0 1 0 0 0 0 - 0 0 0 0 1
[ 5 0 ] D r o u lia s , C ., e t a l. ( 1 9 7 6 ) T h e S u p e r io r L a r y n g e a l N e r v e . T h e A m e r ic a n S u r g e o n ,
4 2 , 6 3 5 -6 3 8 .
[ 5 1 ] P a r a s k e v a s , G .K ., e t a l. ( 2 0 1 2 ) T o p o g r a p h ic A n a to m y o f th e I n te r n a l L a r y n g e a l
N e r v e : S u r g ic a l C o n s id e r a tio n s . H e a d N e c k , 3 4 , 5 3 4 -5 4 0 .
h ttp s :/ / d o i.o r g / 1 0 .1 0 0 2 / h e d .2 1 7 6 9
[ 5 2 ] G r a y , H . ( 2 0 0 8 ) N e c k . I n : S ta n d r in g , S ., E d ., G r a y s A n a to m y : T h e A n a to m ic a l B a s is
o f C lin ic a l P r a c tic e , V o l. 1 , 4 0 th E d itio n , C h u r c h ill L iv in g s to n e , N e w Y o r k , 1 5 7 6 .
[ 5 3 ] H o r iu c h i, M . a n d S a s a k i, C .T . ( 1 9 7 8 ) C r ic o th y r o id M u s c le in R e s p ir a tio n . A n n a ls o f
O to lo g y , R h in o lo g y & L a r y n g o lo g y , 8 7 , 3 8 6 - 3 9 1 .
h ttp s :/ / d o i.o r g / 1 0 .1 1 7 7 / 0 0 0 3 4 8 9 4 7 8 0 8 7 0 0 3 1 8
R. Arrangoiz et al.
[ 5 4 ] C e r n e a , C .R ., e t a l. ( 1 9 9 2 ) S u r g ic a l A n a to m y o f th e E x te r n a l B r a n c h o f th e S u p e r io r
L a r y n g e a l N e r v e . H e a d N e c k , 1 4 , 3 8 0 - 3 8 3 . h ttp s :/ / d o i.o r g / 1 0 .1 0 0 2 / h e d .2 8 8 0 1 4 0 5 0 7
[ 5 5 ] P a g e d a r , N .A . a n d F r e e m a n , J .L . ( 2 0 0 9 ) I d e n tific a tio n o f th e E x te r n a l B r a n c h o f th e
S u p e r io r L a r y n g e a l N e r v e d u r in g T h y r o id e c to m y . A r c h iv e s o f O to la r y n g o lo -
g y — H e a d & N e c k S u r g e r y , 1 3 5 , 3 6 0 - 3 6 2 . h ttp s :/ / d o i.o r g / 1 0 .1 0 0 1 / a r c h o to .2 0 0 9 .9
[ 5 6 ] P o r tu la n o , C ., P a r o d e r - B e le n its k y , M . a n d C a r r a s c o , N . ( 2 0 1 4 ) T h e N a + / I − S y m p o r -
te r ( N IS ) : M e c h a n is m a n d M e d ic a l Im p a c t. E n d o c r in e R e v ie w s , 3 5 , 1 0 6 - 1 4 9 .
h t t p s :/ / d o i.o r g / 1 0 .1 2 1 0 / e r .2 0 1 2 - 1 0 3 6
[ 5 7 ] D u n n , J .T . a n d D u n n , A .D . ( 2 0 0 1 ) U p d a te o n I n tr a th y r o id a l I o d in e M e ta b o lis m .
T h y r o id , 1 1 , 4 0 7 - 4 1 4 . h ttp s :/ / d o i.o r g / 1 0 .1 0 8 9 / 1 0 5 0 7 2 5 0 1 3 0 0 1 7 6 3 6 3
[ 5 8 ] N a tio n a l In s titu te s o f H e a lth ( 2 0 1 6 ) Io d in e F a c t S h e e t fo r C o n s u m e r s .
[ 5 9 ] L e u n g , A .M . a n d B r a v e r m a n , L .E . ( 2 0 1 2 ) I o d in e - I n d u c e d T h y r o id D y s fu n c tio n .
C u r r e n t O p in io n in E n d o c r in o lo g y , D ia b e te s a n d O b e s ity , 1 9 , 4 1 4 - 4 1 9 .
h ttp s :/ / d o i.o r g / 1 0 .1 0 9 7 / M E D .0 b 0 1 3 e 3 2 8 3 5 6 5 b b 2
[ 6 0 ] K o p p , P . ( 2 0 0 5 ) T h y r o id H o r m o n e S y n t h e s is . I n : B r a v e r m a n , L .E . a n d U t ig e r , R .,
E d s ., W e r n e r & I n g b a r ’s th e T h y r o id : A F u n d a m e n ta l a n d C lin ic a l T e x t, L ip p in c o tt
W illia m s & W ilk in s , P h ila d e lp h ia .
[ 6 1 ] D a i, G ., L e v y , O . a n d C a r r a s c o , N . ( 1 9 9 6 ) C lo n in g a n d C h a r a c te r iz a tio n o f th e T h y -
r o id I o d id e T r a n s p o r t e r . N a t u r e , 3 7 9 , 4 5 8 - 4 6 0 . h t t p s :/ / d o i.o r g / 1 0 .1 0 3 8 / 3 7 9 4 5 8 a 0
[ 6 2 ] C a r r a s c o , N .T . ( 2 0 0 5 ) H y r o id I o d in e T r a n s p o r t. I n : B r a v e r m a n , L .E . a n d U tig e r , R .,
E d s ., W e r n e r & I n g b a r ’s th e T h y r o id : A F u n d a m e n ta l a n d C lin ic a l T e x t, L ip p in c o tt
W illia m s & W ilk in s , P h ila d e lp h ia .
[ 6 3 ] R o ti, E . a n d U b e r ti, E .D . ( 2 0 0 1 ) I o d in e E x c e s s a n d H y p e r th y r o id is m . T h y r o id , 1 1 ,
4 9 3 - 5 0 0 . h ttp s :/ / d o i.o r g / 1 0 .1 0 8 9 / 1 0 5 0 7 2 5 0 1 3 0 0 1 7 6 4 5 3
[ 6 4 ] C o lin , I .M ., e t a l. ( 2 0 1 3 ) R e c e n t I n s ig h t s in t o t h e C e ll B io lo g y o f T h y r o id A n g io f o l-
lic u la r U n it s . E n d o c r in e R e v ie w s , 3 4 , 2 0 9 - 2 3 8 . h t t p s :/ / d o i.o r g / 1 0 .1 2 1 0 / e r .2 0 1 2 - 1 0 1 5
[ 6 5 ] F o n g , P . ( 2 0 1 1 ) T h y r o id I o d id e E fflu x : A T e a m E ffo r t? T h e J o u r n a l o f P h y s io lo g y ,
5 8 9 , 5 9 2 9 - 5 9 3 9 . h t t p s :/ / d o i.o r g / 1 0 .1 1 1 3 / jp h y s io l.2 0 1 1 .2 1 8 5 9 4
[ 6 6 ] A r v a n , P . a n d D i J e s o , B . ( 2 0 0 5 ) T h y r o g lo b u lin S tr u c tu r e , F u n c tio n , a n d B io s y n th e -
s is . I n : B r a v e r m a n , L .E . a n d U t ig e r , R ., E d s ., W e r n e r & I n g b a r ’s th e T h y r o id : A
F u n d a m e n ta l a n d C lin ic a l T e x t, L ip p in c o tt W illia m s & W ilk in s , P h ila d e lp h ia ,
7 7 -9 5 .
[ 6 7 ] Y o s h ih a r a , A ., e t a l. ( 2 0 1 2 ) R e g u la tio n o f D u a l O x id a s e E x p r e s s io n a n d H 2 O 2 P ro -
d u c tio n b y T h y r o g lo b u lin . T h y r o id , 2 2 , 1 0 5 4 - 1 0 6 2 .
h t t p s :/ / d o i.o r g / 1 0 .1 0 8 9 / t h y .2 0 1 2 .0 0 0 3
[ 6 8 ] B e lk a d i, A ., e t a l. ( 2 0 1 2 ) P h y lo g e n e tic A n a ly s is o f th e H u m a n T h y r o g lo b u lin R e -
g io n s . T h y r o id R e s e a r c h , 5 , 3 . h t t p s :/ / d o i.o r g / 1 0 .1 1 8 6 / 1 7 5 6 - 6 6 1 4 - 5 - 3
[ 6 9 ] D i J e s o , B ., e t a l. ( 2 0 1 4 ) T r a n s ie n t C o v a le n t I n te r a c tio n s o f N e w ly S y n th e s iz e d T h y -
r o g lo b u lin w ith O x id o r e d u c ta s e s o f th e E n d o p la s m ic R e tic u lu m . T h e J o u r n a l o f B i-
o lo g ic a l C h e m is t r y , 2 8 9 , 1 1 4 8 8 - 1 1 4 9 6 . h t t p s :/ / d o i.o r g / 1 0 .1 0 7 4 / jb c .M 1 1 3 .5 2 0 7 6 7
[ 7 0 ] X ia o , S ., e t a l. ( 1 9 9 6 ) S e le c tiv ity in T y r o s y l I o d in a tio n S ite s in H u m a n T h y r o g lo b u -
lin . A r c h iv e s o f B io c h e m is tr y a n d B io p h y s ic s , 3 3 4 , 2 8 4 - 2 9 4 .
h ttp s :/ / d o i.o r g / 1 0 .1 0 0 6 / a b b i.1 9 9 6 .0 4 5 7
[ 7 1 ] M a r in o , M . a n d M c C lu s k e y , R .T . ( 2 0 0 0 ) R o le o f T h y r o g lo b u lin E n d o c y tic P a th w a y s
in th e C o n tr o l o f T h y r o id H o r m o n e R e le a s e . A m e r ic a n J o u r n a l o f P h y s io lo g y - C e ll
P h y s io lo g y , 2 7 9 , C 1 2 9 5 - C 1 3 0 6 . h t t p s :/ / d o i.o r g / 1 0 .1 1 5 2 / a jp c e ll.2 0 0 0 .2 7 9 .5 .C 1 2 9 5
[ 7 2 ] S c h n e id e r , P .B . ( 1 9 6 4 ) T h y r o id a l I o d in e H e te r o g e n e ity : “ L a s t C o m e , F ir s t S e r v e d ”
R. Arrangoiz et al.
S y s te m o f I o d in e T u r n o v e r . E n d o c r in o lo g y , 7 4 , 9 7 3 - 9 8 0 .
h ttp s :/ / d o i.o r g / 1 0 .1 2 1 0 / e n d o - 7 4 - 6 - 9 7 3
[ 7 3 ] B e r n ie r - V a le n t in , F ., e t a l. ( 1 9 9 0 ) C o a te d V e s ic le s fr o m T h y r o id C e lls C a r r y I o d i-
n a te d T h y r o g lo b u lin M o le c u le s . F ir s t I n d ic a tio n fo r a n I n te r n a liz a tio n o f th e T h y -
r o id P r o h o r m o n e v ia a M e c h a n is m o f R e c e p to r - M e d ia te d E n d o c y to s is . T h e Jo u r n a l
o f B io lo g ic a l C h e m is tr y , 2 6 5 , 1 7 3 7 3 -1 7 3 8 0 .
[ 7 4 ] B o tta , R ., e t a l. ( 2 0 1 1 ) B in d in g , U p ta k e , a n d D e g r a d a tio n o f I n te r n a liz e d T h y r o g lo -
b u lin in C u ltu r e d T h y r o id a n d N o n - T h y r o id C e lls . J o u r n a l o f E n d o c r in o lo g ic a l I n -
v e s tig a tio n , 3 4 , 5 1 5 -5 2 0 .
[ 7 5 ] R o u s s e t, B ., e t a l. ( 1 9 8 9 ) T h y r o id H o r m o n e R e s id u e s A r e R e le a s e d fr o m T h y r o g lo -
b u lin w ith O n ly L im ite d A lte r a tio n o f th e T h y r o g lo b u lin S tr u c tu r e . T h e J o u r n a l o f
B io lo g ic a l C h e m is tr y , 2 6 4 , 1 2 6 2 0 - 1 2 6 2 6 .
[7 6 ] G n id e h o u , S ., e t a l. ( 2 0 0 4 ) Io d o ty r o s in e D e h a lo g e n a s e 1 ( D E H A L 1 ) Is a T r a n s -
m e m b r a n e P r o te in In v o lv e d in th e R e c y c lin g o f I o d id e C lo s e to th e T h y r o g lo b u lin
Io d in a tio n S ite . T h e F A S E B Jo u r n a l, 1 8 , 1 5 7 4 - 1 5 7 6 .
h ttp s :/ / d o i.o r g / 1 0 .1 0 9 6 / fj.0 4 - 2 0 2 3 fje
[7 7 ] G n id e h o u , S ., e t a l. ( 2 0 0 6 ) C lo n in g a n d C h a r a c te r iz a tio n o f a N o v e l Is o fo r m o f
Io d o ty ro s in e D e h a lo g e n a s e 1 (D E H A L 1 ) D E H A L 1 C fr o m H u m a n T h y r o id : C o m -
p a r is o n s w ith D E H A L 1 a n d D E H A L 1 B . T h y r o id , 1 6 , 7 1 5 -7 2 4 .
h ttp s :/ / d o i.o r g / 1 0 .1 0 8 9 / th y .2 0 0 6 .1 6 .7 1 5
[ 7 8 ] D u n n , A .D ., C r u t c h f ie ld , H .E . a n d D u n n , J .T . ( 1 9 9 1 ) T h y r o g lo b u lin P r o c e s s in g b y
T h y r o id a l P r o te a s e s . M a jo r S ite s o f C le a v a g e b y C a th e p s in s B , D , a n d L . T h e Jo u r n a l
o f B io lo g ic a l C h e m is tr y , 2 6 6 , 2 0 1 9 8 - 2 0 2 0 4 .
[7 9 ] D u n n , A .D ., M y e r s , H .E . a n d D u n n , J .T . ( 1 9 9 6 ) T h e C o m b in e d A c tio n o f T w o
T h y r o id a l P r o te a s e s R e le a s e s T 4 fr o m th e D o m in a n t H o r m o n e -F o r m in g S ite o f
T h y r o g lo b u lin . E n d o c r in o lo g y , 1 3 7 , 3 2 7 9 -3 2 8 5 .
h ttp s :/ / d o i.o r g / 1 0 .1 2 1 0 / e n d o .1 3 7 .8 .8 7 5 4 7 5 1
[ 8 0 ] D i C o s m o , C ., e t a l. ( 2 0 1 0 ) M ic e D e fic ie n t in M C T 8 R e v e a l a M e c h a n is m R e g u la tin g
T h y r o id H o r m o n e S e c r e tio n . Jo u r n a l o f C lin ic a l I n v e s tig a tio n , 1 2 0 , 3 3 7 7 - 3 3 8 8 .
h ttp s :/ / d o i.o r g / 1 0 .1 1 7 2 / J C I 4 2 1 1 3
[ 8 1 ] F r ie s e m a , E .C ., e t a l. ( 2 0 0 6 ) T h y r o id H o r m o n e T r a n s p o r t b y th e H u m a n M o n o c a r -
b o x y la te T r a n s p o r te r 8 a n d I ts R a te - L im itin g R o le in I n tr a c e llu la r M e ta b o lis m . M o -
le c u la r E n d o c r in o lo g y , 2 0 , 2 7 6 1 - 2 7 7 2 . h ttp s :/ / d o i.o r g / 1 0 .1 2 1 0 / m e .2 0 0 5 - 0 2 5 6
[ 8 2 ] S ta th a to s , N . ( 2 0 1 2 ) T h y r o id P h y s io lo g y . M e d ic a l C lin ic s o f N o r th A m e r ic a , 9 6 ,
1 6 5 - 1 7 3 . h t t p s :/ / d o i.o r g / 1 0 .1 0 1 6 / j.m c n a .2 0 1 2 .0 1 .0 0 7
[ 8 3 ] B a r ta le n a , L . a n d R o b b in s , J . ( 1 9 9 3 ) T h y r o id H o r m o n e T r a n s p o r t P r o te in s . C lin ic s
in L a b o r a to r y M e d ic in e , 1 3 , 5 8 3 -5 9 8 .
[ 8 4 ] B e n v e n g a , S . ( 2 0 0 5 ) T h y r o id H o r m o n e T r a n s p o r t P r o te in s a n d th e P h y s io lo g y o f
H o r m o n e B in d in g . I n : B r a v e r m a n , L .E . a n d U tig e r , R ., E d s ., W e r n e r & I n g b a r ’s th e
T h y r o id : A F u n d a m e n ta l a n d C lin ic a l T e x t, L ip p in c o tt W illia m s & W ilk in s , P h ila -
d e lp h ia .
[ 8 5 ] S c h u s s le r , G .C . ( 2 0 0 0 ) T h e T h y r o x in e - B in d in g P r o te in s . T h y r o id , 1 0 , 1 4 1 - 1 4 9 .
h t t p s :/ / d o i.o r g / 1 0 .1 0 8 9 / t h y .2 0 0 0 .1 0 .1 4 1
[ 8 6 ] F u , J . a n d D u m itr e s c u , A .M . ( 2 0 1 4 ) I n h e r ite d D e fe c ts in T h y r o id H o r m o n e
C e ll- M e m b r a n e T r a n s p o r t a n d M e ta b o lis m . B e s t P r a c tic e & R e s e a r c h : C lin ic a l E n -
d o c r in o lo g y & M e t a b o lis m , 2 8 , 1 8 9 - 2 0 1 . h t t p s :/ / d o i.o r g / 1 0 .1 0 1 6 / j.b e e m .2 0 1 3 .0 5 .0 1 4
[ 8 7 ] D e n tic e , M ., e t a l. ( 2 0 1 3 ) T h e D e io d in a s e s a n d th e C o n tr o l o f I n tr a c e llu la r T h y r o id
H o r m o n e S ig n a lin g d u r in g C e llu la r D iffe r e n tia tio n . B io c h im ic a e t B io p h y s ic a A c ta ,
R. Arrangoiz et al.
1 8 3 0 , 3 9 3 7 - 3 9 4 5 . h t t p s :/ / d o i.o r g / 1 0 .1 0 1 6 / j.b b a g e n .2 0 1 2 .0 5 .0 0 7
[ 8 8 ] M a ia , A .L ., e t a l. ( 2 0 1 1 ) D e io d in a s e s : T h e B a la n c e o f T h y r o id H o r m o n e : T y p e 1
Io d o th y r o n in e D e io d in a s e in H u m a n P h y s io lo g y a n d D is e a s e . Jo u r n a l o f E n d o c r i-
n o lo g y , 2 0 9 , 2 8 3 - 2 9 7 . h ttp s :/ / d o i.o r g / 1 0 .1 5 3 0 / J O E - 1 0 - 0 4 8 1
[ 8 9 ] C h e n g , S .Y ., L e o n a r d , J .L . a n d D a v is , P .J . ( 2 0 1 0 ) M o le c u la r A s p e c t s o f T h y r o id
H o r m o n e A c tio n s . E n d o c r in e R e v ie w s , 3 1 , 1 3 9 - 1 7 0 .
h t t p s :/ / d o i.o r g / 1 0 .1 2 1 0 / e r .2 0 0 9 - 0 0 0 7
[ 9 0 ] B r e n t, G .A . ( 2 0 1 2 ) M e c h a n is m s o f T h y r o id H o r m o n e A c tio n . J o u r n a l o f C lin ic a l
I n v e s tig a tio n , 1 2 2 , 3 0 3 5 - 3 0 4 3 . h ttp s :/ / d o i.o r g / 1 0 .1 1 7 2 / J C I 6 0 0 4 7
[ 9 1 ] H o lle n b e r g , A .N . ( 2 0 0 8 ) T h e R o le o f t h e T h y r o t r o p in - R e le a s in g H o r m o n e ( T R H )
N e u r o n a s a M e ta b o lic S e n s o r . T h y r o id , 1 8 , 1 3 1 - 1 3 9 .
h t t p s :/ / d o i.o r g / 1 0 .1 0 8 9 / t h y .2 0 0 7 .0 2 5 1
[ 9 2 ] S e llit t i, D .F . a n d S u z u k i, K . ( 2 0 1 4 ) I n t r in s ic R e g u la t io n o f T h y r o id F u n c t io n b y
T h y r o g lo b u lin . T h y r o id , 2 4 , 6 2 5 - 6 3 8 . h t t p s :/ / d o i.o r g / 1 0 .1 0 8 9 / t h y .2 0 1 3 .0 3 4 4
[ 9 3 ] Z o e lle r , R .T ., T a n , S .W . a n d T y l, R .W . ( 2 0 0 7 ) G e n e r a l B a c k g r o u n d o n th e H y p o th a -
la m ic - P itu ita r y - T h y r o id ( H P T ) A x is . C r itic a l R e v ie w s in T o x ic o lo g y , 3 7 , 1 1 - 5 3 .
h ttp s :/ / d o i.o r g / 1 0 .1 0 8 0 / 1 0 4 0 8 4 4 0 6 0 1 1 2 3 4 4 6
[ 9 4 ] M a r k o u , K ., e t a l. ( 2 0 0 1 ) I o d in e - I n d u c e d H y p o th y r o id is m . T h y r o id , 1 1 , 5 0 1 - 5 1 0 .
h ttp s :/ / d o i.o r g / 1 0 .1 0 8 9 / 1 0 5 0 7 2 5 0 1 3 0 0 1 7 6 4 6 2
[ 9 5 ] R o s s , M .H . a n d P a w lin a , W . ( 1 9 8 5 ) E n d o c r in e O r g a n s : T h y r o id G la n d . I n : H is to lo -
g y : A T e x t a n d A tla s w ith C o r r e la te d C e ll a n d M o le c u la r H is to lo g y , V o l. 1 , 6 th E d i-
tio n , W o lte r s K lu w e r / L ip p in c o tt W illia m s a n d W ilk in s , N e w Y o r k .
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Comprehensive Reviewof Thyroid Embryology Anatomy Histologyand Physiologyfor Surgeons

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Comprehensive Review of Thyroid Embryology, Anatomy, Histology, and

Rodrigo Arrangoiz Fernando Cordera

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Manuel Muñoz Eduardo Moreno

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Comprehensive Review of Thyroid Embryology,

Rodrigo Arrangoiz*, Fernando Cordera, David Caba, Manuel Muñoz,

2. Thyroid Gland Embryogenesis

F ig u r e 2 . T h y r o id F o llic le s a n d th y r o id p a r a fo llic u la r o r C c e lls .

3. Thyroid Gland Histology

T a b le 1 . A c tio n s o f th e th y r o id fo llic u la r c e lls [ 9 5 ] .

T h e s e c o n d g r o u p o f th y r o id s e c r e to r y c e lls is th e p a r a fo llic u la r o r C c e lls , d e -

4. Thyroid Gland Anatomy

F ig u r e 6 . T h e ly m p h a tic d r a in a g e o f th e th y r o id g la n d is e x te n s iv e a n d flo w s in a m u lti-

5. Thyroid Gland Physiology

r e s id u e s [ 5 7 ] [ 6 4 ] [ 7 1 ] . W h e n th e th y r o id fo llic u la r c e lls a r e s tim u la te d b y th y -

c a lle d th y r o tr o p in o r th y r o id s tim u la tin g h o r m o n e ) is s y n th e s iz e d a n d s e c r e te d .

S u r v e y ( N H A N E S I I I ) . T h e Jo u r n a l o f C lin ic a l E n d o c r in o lo g y & M e ta b o lis m , 8 7 ,

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