Multinodular Goiter: Diagnosis and Management.

DISEASES OF
THE THYROID
Pathophysiology and
management
Edited by
Malcolm H. Wheeler
Consultant
Surgeon
University Hospital of Wales
Cardiff Royal
Infirmary
Cardiff
MD
(Wales), FRCS (Eng)
and
Wales
UK
and
John H. Lazarus ,
MA
Senior Lecturer and Consultant
University of Wales College of
Cardiff
Wales
UK
M D ( C a n t a b ) F R C P ( L o n d a n d Glas)
Physician
Medicine
CHAPMAN & HALL
London • Glasgow • Weinheim • New York • Tokyo • Melbourne • Madras
Published by Chapman & Hall,
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First edition 1994
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CONTENTS
L i s t of c o n t r i b u t o r s
ix
F o r e w o r d b y Sir Richard
I. S. Bayliss,
K C V O , MD, FRCP
Preface
xiii
xv
1 T h e E v o l u t i o n of T r e a t m e n t of T h y r o i d D i s e a s e
(a) M e d i c a l aspects
Reg Hall
(b) H i s t o r y o f t h y r o i d s u r g e r y
Barnard j. Harrison and Richard B.
11
Welbourn
2 T h y r o i d Physiology
19
(a) T h y r o i d h o r m o n e p r o d u c t i o n , t r a n s p o r t a n d m e t a b o l i s m
Georg Hennemann,
RoelofDocter
and Eric P.
29
Franklyn
(c) T h y r o i d cell g r o w t h
Allan E. Siperstein and Orlo H.
41
Clark
3 E t i o l o g y of B e n i g n T h y r o i d D i s e a s e
(a) E p i d e m i o l o g y
Gordon Caldwell
I. W.
51
53
and Michael
Tunbridge
(b) G e n e t i c factors
David
21
Krenning
(b) T h y r o i d h o r m o n e a c t i o n
Jayne A.
1
3
61
Phillips
(c) E n v i r o n m e n t a l aspects
Eduardo
Gaitan
73
(d) I m m u n o l o g i c a l factors
Philip S. Barnett and Alan M.
85
McGregor
4 D i a g n o s t i c T e s t s of T h y r o i d F u n c t i o n a n d Structure
(a) H o r m o n e m e a s u r e m e n t s
Rhys John and John H.
Lazarus
105
107
VI
Contents
(b) T h y r o i d a n t i b o d i e s
Jadwiga Furmaniak and Bernard
117
Rees
Smith
(c) T h y r o i d imaging
Michael N. Maisey
131
(d) F i n e n e e d l e a s p i r a t i o n c y t o l o g y
Ronald H. Nishiyama, S. Thomas Bigos and Daniel S.
153
Oppenheim
163
165
5 Hyperthyroidism
(a) C l i n i c a l f e a t u r e s
John H. Lazarus
(b) G r a v e s ' disease
Anthony P. Weetman
171
(c) T h e t o x i c s o l i t a r y n o d u l e a n d t o x i c m u l t i n o d u l a r g o i t e r
193
Hans
Bürgi
( d ) O t h e r causes o f h y p e r t h y r o i d i s m
John H.
(e) S u r g e r y f o r h y p e r t h y r o i d i s m
Malcolm
201
Lazarus
H.
207
Wheeler
6 M u l t i n o d u l a r Goiter: Diagnosis and Management
C. Renate Pickardt and Peter C. Scriba
219
7 T h e Solitary Thyroid Nodule
231
Malcolm
H.
Wheeler
8 H y p o t h y r o i d i s m : Etiology a n d M a n a g e m e n t
Nobuyuki Amino and Junko Tachi
245
9 T h y r o i d Disease and Pregnancy
269
John H.
Lazarus
10 E t i o l o g y of T h y r o i d C a n c e r
(a) M o l e c u l a r genetics
Raj V. Thakker
281
283
(b) G r o w t h factors a n d o n c o g e n e s
David
299
Wynford-Thomas
(c) R a d i a t i o n - a s s o c i a t e d t h y r o i d c a r c i n o m a
/. Francisco Fierro-Renoy and Leslie J. DeGroot
11 P a t h o l o g y of T h y r o i d C a n c e r
H. Ruben Harach and Sir E. Dillwyn
325
343
Williams
12 C l i n i c a l Features a n d M a n a g e m e n t of T h y r o i d C a n c e r
(a) D i f f e r e n t i a t e d t h y r o i d c a r c i n o m a
Norman W. Thompson
(b) A n a p l a s t i c g i a n t cell t h y r o i d c a r c i n o m a
Martin Bäckdahl, Bertil Hamberger, Torsten
Löwhagen
and Göran
Lundell
(c) M a l i g n a n t l y m p h o m a o f t h e t h y r o i d
Charles /.
Edmonds
(d) M e d u l l a r y t h y r o i d c a r c i n o m a
Jon A. van Heerden and Ian D.
Hay
(e) M a n a g e m e n t o f m e t a s t a t i c t h y r o i d cancer
Martin
Schlumberger
( f ) P r o g n o s t i c factors a n d D N A p l o i d y d e t e r m i n a t i o n i n d i f f e r e n t i a t e d
t h y r o i d carcinoma
lan D.
Index
Hay
MULTINODULAR GOITER: DIAGNOSIS
A N D MANAGEMENT
6
C. Renate Pickardt and Peter C. Scriba
Multinodular
thyroid
enlargement
is
a
s y m p t o m of d i f f e r e n t t h y r o i d diseases w i t h
varying u n d e r l y i n g pathogenetic principles
(Table 6.1). F r o m t h e e p i d e m i o l o g i c a l p o i n t
of v i e w , endemic a n d sporadic goiters have
to be d i s t i n g u i s h e d . G o i t e r e n d e m i a
is
assumed by definition i n regions w i t h a
p r e v a l e n c e of m o r e t h a n 10% a m o n g t h e
population u n d e r investigation [1].
I n m o s t e n d e m i c areas, i o d i n e d e f i c i e n c y
is the m a i n cause o f g o i t e r d e v e l o p m e n t .
A n o t h e r cause of g o i t e r e n d e m i a is t h e
i n t a k e of g o i t r o g e n s v i a t h e d r i n k i n g w a t e r
as
in
Columbia
and
the
Himalayas
( C h a p t e r 3(c)). I n o t h e r r e g i o n s i o d i n e d e ficiency a n d dietary goitrogens f r o m vegetable f o o d s t u f f s are t o g e t h e r r e s p o n s i b l e f o r
t h i s k i n d o f e n d e m i c disease [ 2 ] , w h i c h is
best d o c u m e n t e d for Z a i r e . V e g e t a b l e s w i t h
g o i t r o g e n i c effect c o n t a i n t h i o g l y c o s i d e s o r
cyanogenic
glycosides.
In
this
context
cigarette s m o k i n g is t h o u g h t to be a cofactor
for g o i t r o g e n e s i s , since i t increases s e r u m
thiocyanate
concentration.
Regions
with
i o d i n e d e f i c i e n c y a n d e n d e m i c g o i t e r are
f o u n d all o v e r t h e w o r l d , p a r t i c u l a r l y i n
m o u n t a i n o u s areas a n d c o n t i n e n t a l r e g i o n s ,
w h e r e i o d i n e p r o p h y l a x i s is n o t u s e d [ 1 , 3 ] .
T h e k n o w n data c o n c e r n i n g t h e s e v e r i t y a n d
d e g r e e of i o d i n e d e f i c i e n c y a n d g o i t e r p r e v a lence i n E u r o p e are s h o w n i n F i g u r e s 6 . 1 ,
6.2. U S A , C a n a d a a n d Japan a n d t h e coastal
areas o f a l l c o n t i n e n t s are free o f i o d i n e
d e f i c i e n c y diseases. I n i o d i n e d e f i c i e n t r e g i o n s , i o d i n e i n s u f f i c i e n c y is t h e m o s t p r o b able cause of g o i t e r . B u t n e i t h e r m o r p h o l o g i c a l n o r f u n c t i o n a l c r i t e r i a can d i s c r i m i n a t e
specifically between endemic a n d sporadic
g o i t e r i n a n affected i n d i v i d u a l .
S p o r a d i c g o i t e r can be d i v i d e d i n t o cases
w i t h a genetic b a c k g r o u n d , i n c l u d i n g i n d i v i d u a l s w i t h c o n g e n i t a l goiters i n n o n e n d e m i c areas, a n d o t h e r cases i n d u c e d b y
g o i t r o g e n i c d r u g s . S p o n t a n e o u s cases m a y
also arise f r o m t h y r o i d i t i s or g r o w t h s t i m u l a t i n g g l o b u l i n s , especially w h e n t h y r o i d
e n l a r g e m e n t occurs s u d d e n l y . The d i f f e r e n t
g e n e t i c defects o f t h y r o i d h o r m o n e s y n t h e s i s
Table 6.1 Causes of multinodular goiter
Endemic
Sporadic
Iodine deficiency
Dietary goitrogens
Environmental goitrogens
Diseases
of the Thyroid.
Genetic defects of thyroid hormone synthesis
Genetic defects of thyroid hormone action
Goitrogenic drugs
Thyroiditis syndromes
Acromegaly
TSH producing pituitary adenoma
Edited by M a l c o l m H . Wheeler and John H . Lazarus. Published i n
1994 b y C h a p m a n & H a l l , L o n d o n . I S B N 0 412 43030 4 .
220
Multinodular
goiter
o r t h y r o i d h o r m o n e a c t i o n ( T r e c e p t o r defect)
are rare causes of g o i t e r f o r m a t i o n , w h i c h
can h o w e v e r r e s u l t i n m u l t i n o d u l a r g o i t e r i n
a f f e c t e d f a m i l i e s . I n t h e m i n o r f o r m s of these
defects t h e r e m a y be c o m p e n s a t i o n of t h y r o i d f u n c t i o n so t h a t t h e i n d i v i d u a l r e m a i n s
e u t h y r o i d , w h e r e a s t h e m a j o r f o r m s w i l l be
detected by evidence of h y p o t h y r o i d i s m and
goiter or even cretinism early i n the childhood.
4
Sporadic goiter i n d u c e d b y d r u g s interferi n g w i t h t h y r o i d h o r m o n e s y n t h e s i s or release is n o w a rare e v e n t . T h i s is d u e to t h e
fact t h a t i n d i c a t i o n s f o r a n t i t h y r o i d d r u g
t r e a t m e n t are e s t a b l i s h e d , dosage f o r h y p e r t h y r o i d i s m is easy t o c o n t r o l , a n d side
effects o f substances such as l i t h i u m , c a r b u t a m i d e , f l u o r i d e a n d a m i n o g l u t e t h i m i d e are
w e l l recognized i n medical practice.
Figure 6.1 Urinary iodine excretion (^tg/g creatinine); updated map of the original publication
[4]. (Regional values are denoted i n brackets.)
Figure 6.2 Goiter prevalence (%); updated map
of the original publication [4]. (Regional values
are denoted i n brackets.)
I o d i n e i n d u c e d g o i t e r s are o b s e r v e d m a i n l y i n l i m i t e d areas i n J a p a n , w h e r e excessive
i n t a k e of s e a w e e d is t h o u g h t t o be r e s p o n s i b l e f o r a defect of t h e escape f r o m the
W o l f f - C h a i k o f f effect. T h i s p o p u l a t i o n m a y
develop hypothyroidism.
A n acute d e v e l o p m e n t of m u l t i n o d u l a r
g o i t e r gives rise to t h e s u s p i c i o n of i n f l a m m a t o r y t h y r o i d disease, w h i c h is p a i n f u l
i n t h e case of acute t h y r o i d i t i s a n d t h e
s u b a c u t e t h y r o i d i t i s of D e Q u e r v a i n , or p a i n less i n the case of g r a n u l o m a t o u s diseases
s u c h as sarcoidosis o r t u b e r c u l o s i s .
I n g e n e r a l , n o d u l a r t r a n s f o r m a t i o n of t h e
e n l a r g e d t h y r o i d is t h e c o n s e q u e n c e of earlier d i f f u s e t h y r o i d e n l a r g e m e n t u n d e r t h e
c o n t i n u i n g influence of the goitrogenic p r i n ciple [5,6]. Therefore, patients w i t h m u l t i n o d u l a r g o i t e r u s u a l l y are o l d e r t h a n those
w i t h d i f f u s e t h y r o i d e n l a r g e m e n t [ 5 , 7 ] . I t has
b e e n s h o w n f o r s p o r a d i c g o i t e r t h a t t h e r e is
a l i n e a r r e l a t i o n s h i p b e t w e e n age a n d t h y r oid v o l u m e and n o d u l a r i t y , respectively,
w i t h a n average y e a r l y increase of 4 . 5 % of
g o i t e r v o l u m e , as c a l c u l a t e d b y B e r g h o u t , et
al.
[5,8]. D u r i n g n o d u l a r transformation
hypo-,
normal,
and
hyperfunctioning
n o d u l e s m a y d e v e l o p w i t h i n the same
Clinical
gland. Also, multiple autonomously funct i o n i n g n o d u l e s can be o b s e r v e d i n m u l t i n o d u l a r g o i t e r s w i t h associated e u t h y r o i d i s m . T h i s so-called m u l t i f o c a l f u n c t i o n a l
a u t o n o m y is a disease w i t h a r e l a t i v e l y h i g h
frequency i n regions w i t h endemic goiter,
b u t l i t t l e a t t e n t i o n has b e e n p a i d to t h i s f i n a l
c o n s e q u e n c e of c h r o n i c i o d i n e d e f i c i e n c y . A s
l o n g as i o d i n e d e f i c i e n c y persists, these p a tients o f t e n r e m a i n frequently e u t h y r o i d or
develop borderline hyperthyroidism. O n l y
w h e n t h e a m o u n t of a u t o n o m o u s l y f u n c t i o n i n g tissue is h i g h does s p o n t a n e o u s h y p e r t h y r o i d i s m occur. H o w e v e r , t h i s g r o u p o f
p a t i e n t s bears a n u n k n o w n risk of i o d i n e
i n d u c e d h y p e r t h y r o i d i s m w h e n t h e r e is a
b r i s k a n d / o r p r o l o n g e d increase o f i o d i n e
intake (Chapter 5(d)). I n o u r hospital, this
disease is t w i c e as o f t e n the cause o f h y p e r t h y r o i d i s m as i m m u n o g e n i c t h y r o i d disease.
6.1
CLINICAL PICTURE
I n e n d e m i c g o i t r o u s areas, the m e d i c a l h i s t o r y of m u l t i n o d u l a r g o i t e r reveals a l o n g s t a n d i n g t h y r o i d e n l a r g e m e n t i n m o s t cases
[9,10]. A s l o n g as t h e p a t i e n t has n o signs o r
s y m p t o m s of t h y r o i d d y s f u n c t i o n a n d no
local c o m p l i c a t i o n s , t h e disease is o f t e n u n n o t i c e d a n d m a y be detected j u s t b y c h a n c e .
I n o t h e r cases, i n c r e a s i n g g r o w t h of t h e
w h o l e o r g a n , or of o n e or m o r e n o d u l e s , is
r e s p o n s i b l e f o r local s y m p t o m s (Table 6.2)
a n d b r i n g s t h e p a t i e n t to m e d i c a l a t t e n t i o n .
T h i s h i s t o r y is t y p i c a l of e n d e m i c g o i t e r i n
i o d i n e d e f i c i e n t r e g i o n s as w e l l as f o r e n d e m i c g o i t e r i n areas w i t h a s i g n i f i c a n t i n t a k e
of goitrogens. D e p e n d i n g o n the degree of
i o d i n e d e f i c i e n c y or d i e t a r y i n t a k e o f g o i t r o g e n s , p a t i e n t s m a y be e u t h y r o i d or h a v e
m o r e o r less p r o n o u n c e d signs of h y p o t h y r o i d i s m . I n European countries w i t h m i l d
i o d i n e d e f i c i e n c y , t h e g o i t r o u s p o p u l a t i o n is
e u t h y r o i d w i t h f e w exceptions [ 3 , 1 1 ] . O t h e r
causes o f m u l t i n o d u l a r g o i t e r , s u c h as defect i v e t h y r o i d h o r m o n e synthesis or h o r m o n e
a c t i o n , i n d u c e g r a d u a l a n d d i f f e r i n g degrees
picture
221
Table 6.2 Clinical symptoms of
multinodular goiter
Feeling of tightness
Feeling of a foreign body
Dysphagia
Urge to cough
Hoarseness
Dyspnea, stridor
Upper venous obstruction
of h y p o t h y r o i d i s m . I n the more complete
f o r m s o f these g e n e t i c a l l y d e t e r m i n e d d i s eases t h e affected i n d i v i d u a l s are o v e r t l y
h y p o t h y r o i d . Patients w i t h s p o r a d i c g o i t e r
d u e t o d r u g s are also u s u a l l y e u t h y r o i d . I n
lithium
treated
individuals,
however,
h y p o t h y r o i d i s m has b e e n o b s e r v e d . T h e rare
c o n d i t i o n of T S H - p r o d u c i n g p i t u i t a r y t u m o r
has a l r e a d y b e e n d i s c u s s e d . Patients w i t h
a c r o m e g a l y a n d g o i t e r are e u t h y r o i d .
Symptoms
from
nodular
goiter
are
s u m m a r i z e d i n Table 6.2. A f e e l i n g o f t i g h t ness o r of a f o r e i g n b o d y m a y be n o n specific a n d i n d e p e n d e n t o f t h e a c t u a l t h y r o i d v o l u m e or n o d u l e s ; these c o m p l a i n t s
m a y d r a w the a t t e n t i o n of the patient a n d
h i s m e d i c a l a t t e n d a n t to t h e t h u s i n c i d e n t a l l y d e t e c t e d disease. D y s p h a g i a a n d a n u r g e
t o c o u g h m a y r e s u l t also f r o m r e t r o t r a c h e a l
t h y r o i d tissue w h i c h m a y be d e t e c t e d o n l y
b y t h e s u r g e o n . H o a r s e n e s s can be a s i g n o f
functional i m p a i r m e n t of the
recurrent
laryngeal nerve; this functional i m p a i r m e n t
can also be i n d u c e d s p o n t a n e o u s l y i n rare
cases b y b e n i g n t h y r o i d n o d u l e s . D y s p n e a
a n d s t r i d o r m a y be d u e t o tracheal c o m p r e s s i o n or d i s l o c a t i o n b y e p i s t e r n a l o r i n t r a t h o r a c i c g o i t e r s . B o t h t r u e a n d false e n d o t h o r a c i c g o i t e r c a n cause c o m p r e s s i o n o f
the u p p e r venous system, accompanied b y a
m o r e o r less p r o n o u n c e d v e n o u s b y p a s s o f
t h e v e n t r a l thoracic w a l l ( F i g u r e 6.3). Socalled d o w n h i l l varicosis o f t h e e s o p h a g u s
u s u a l l y r e m a i n s s y m p t o m l e s s ( F i g u r e 6.4).
Patients w i t h acute a n d s u b a c u t e t h y r o i d i tis p r e s e n t w i t h a p a i n f u l e n l a r g e d g o i t e r ;
pain usually disseminates over the neck to
222
Multinodular
goiter
t h e ears or t e e t h . P a l p a t i o n of t h e n o d u l e s
intensifies the p a i n . I n chronic i n f l a m m a t o r y
diseases, s u c h as sarcoidosis, t h e n o d u l e s
are painless a n d local s y m p t o m s d o n o t
d i f f e r f r o m t h o s e of e n d e m i c g o i t e r . W i t h
respect to t h e u s u a l l y s h o r t h i s t o r y of these
n o d u l a r g o i t e r s , t h y r o i d m a l i g n a n c y also has
to be c o n s i d e r e d .
6.2
DIAGNOSTIC PROCEDURES
6.2.1 P A L P A T I O N A N D I N V E S T I G A T I O N BY
ULTRASOUND
D i a g n o s t i c p r o c e d u r e s are s u m m a r i z e d i n
Table 6.3. C o n v e n t i o n a l l y , t h e m u l t i n o d u l a r
t h y r o i d is d e t e c t e d b y s i m p l e p a l p a t i o n [ 7 9,12]. W e p e r f o r m p a l p a t i o n s t a n d i n g beh i n d the s i t t i n g p a t i e n t . I n t h i s w a y , t h y r o i d
tissue can be d e f i n e d b y t h e m o v e m e n t
i n d u c e d b y s w a l l o w i n g a g u l p of w a t e r .
N o d u l a r i t y can be d e t e c t e d a n d d e s c r i b e d
separately f o r each lobe a n d f o r t h e t h y r o i d
i s t h m u s , w h i l e also n o t i c i n g t h e c o n s i s t e n c y .
I t is o f i m p o r t a n c e to state w h e t h e r t h e l o w e r
p o l e can be d e f i n e d clearly i n t h e e p i s t e r n a l
p a r t of t h e n e c k , t h u s g e n e r a l l y e x c l u d i n g
e n d o t h o r a c i c p a r t s of t h e t h y r o i d .
Figure 6.4 So-called d o w n h i l l varicosis of the
esophagus i n a patient w i t h recurrent goiter.
Historically,
goiter
size
is
estimated
a c c o r d i n g to t h e W H O c l a s s i f i c a t i o n (Table
6.4) w h i c h w a s o r i g i n a l l y p r o p o s e d f o r
epidemiological purposes. Today, individual
g o i t e r size can be e s t i m a t e d w i t h greater
Diagnostic
Table 6.3
procedures
223
Diagnostic procedure
Palpation
H i g h resolution ultrasonography
Adequate evaluation of thyroid function (basal TSH, FT FT )
Radioisotopic scintiscan (with quantitative evaluation of Tc uptake;
in special situations, radioiodine scan)
Cytologic evaluation of fine needle biopsy
Appropriate evaluation of local complications
4/
3
Table 6.4 Estimation of thyroid size, W H O classification
Stage
0-A
0-B
I
II
III
Clinical findings
N o goiter
Goiter detectable only by palpation and not visible even w h e n the neck
is fully extended
Goiter palpable, but visible only w h e n the neck is fully extended; this
stage also includes nodular glands, even if not goitrous
Goiter visible w i t h the neck i n normal position; palpation is not needed
for diagnosis
Very large goiter w h i c h can be recognized at a considerable distance
accuracy a n d r e p r o d u c i b i l i t y b y u l t r a s o u n d
investigation [6,11-15]. Thickness,
width
a n d l e n g t h of b o t h t h y r o i d lobes h a v e to be
m e a s u r e d . T h e t h y r o i d v o l u m e can t h e n be
calculated b y the f o r m u l a f o r a n e l l i p s o i d
u s i n g an e m p i r i c a l c o r r e c t i o n factor of 0.479
o r 11/6, r e s p e c t i v e l y [ 6 ] . T h e f o r m u l a is:
v o l u m e = a . b . c . 11/6
w h e r e a is the m a x i m a l l e n g t h , b the m a x i m al w i d t h a n d c the m a x i m a l t h i c k n e s s .
I f the i n v e s t i g a t o r has s o m e e x p e r t i s e , the
r e p r o d u c i b i l i t y is s u f f i c i e n t f o r c l i n i c a l p u r poses. T h e d e v i a t i o n o f t h e results is ± 1 0 % .
T h i s m e t h o d has l i m i t a t i o n s i n large n o d u l a r
goiters, w h e r e c o u p l i n g of the transducer to
t h e neck surface m a y n o t be feasible, a n d i n
patients w i t h endothoracic t h y r o i d tissue.
E v a l u a t i o n of n o d u l a r i t y i n a t h y r o i d w i t h
n o r m a l or e n l a r g e d v o l u m e [5,9,11,14,16,17]
can be p e r f o r m e d w i t h a m u c h h i g h e r sensitivity by high resolution ultrasonography
w h e n compared w i t h p a l p a t i o n . By this
m e t h o d , i n patients w i t h u n i n o d u l a r thyr-
oids o n palpation, m u l t i n o d u l a r i t y was
d o c u m e n t e d w i t h a f o u r t i m e s h i g h e r sensit i v i t y as s h o w n b y H a y a n d c o - w o r k e r s [14].
M o r e o v e r , by this m e t h o d , s o n o m o r p h o l o gical c r i t e r i a can be u s e d t o d i f f e r e n t i a t e
b e t w e e n s o l i d , cystic a n d m i x e d s o l i d a n d
cystic n o d u l e s . A m o n g t h e s o l i d n o d u l e s ,
t h o s e o f h i g h or n o r m a l e c h o g e n e i t y can be
distinguished
f r o m those w i t h
reduced
e c h o g e n e i t y b y c o m p a r i s o n w i t h the n o r m a l
t h y r o i d a n d the n e i g h b o r i n g m u s c u l a r t i s sue. T h i s m a y be h e l p f u l i n d e t e r m i n i n g t h e
n o d u l e ( s ) t o be i n v e s t i g a t e d f u r t h e r b y f i n e
n e e d l e a s p i r a t i o n t o e x c l u d e or c o n f i r m
m a l i g n a n c y [18], b u t i t has t o be e m p h a s i z e d
t h a t t h e s o n o m o r p h o l o g i c a l a p p e a r a n c e of a
n o d u l e per
se n e v e r d e f i n i t e l y e x c l u d e s
malignancy.
I n patients w i t h t h y r o i d i t i s , all t h y r o i d
nodules appear hypo-echogenic. W h e n i n f l a m m a t o r y t h y r o i d disease is a s s u m e d ,
w h i t e b l o o d cell c o u n t a n d d e t e r m i n a t i o n o f
t h e ESR can be h e l p f u l . I n p a t i e n t s w i t h
acute t h y r o i d i t i s d u e t o b a c t e r i a l i n f e c t i o n , o r
224
Multinodular
goiter
i n those w i t h suspicion of a g r a n u l o m a t o u s
i n f l a m m a t i o n , general investigations have to
be p e r f o r m e d because d i s s e m i n a t e d m a n i f e s t a t i o n s h a v e t o be e x c l u d e d .
6.2.2
E V A L U A T I O N OF T H Y R O I D F U N C T I O N
The diagnosis comprises appropriate evaluat i o n o f t h y r o i d f u n c t i o n . For p r a c t i c a l p u r poses, a n o r m a l basal T S H l e v e l , w h e n
d e t e r m i n e d b y a s e n s i t i v e assay s y s t e m ,
p r o v i d e s t h e i n f o r m a t i o n t h a t t h e p a t i e n t is
e u t h y r o i d . A n e l e v a t e d basal T S H has t o be
expected i n a patient w i t h decreased t h y r o i d
h o r m o n e effect o r w i t h i m p a i r e d t h y r o i d
h o r m o n e synthesis, whereas completely or
p a r t i a l l y s u p p r e s s e d T S H w i l l i n d i c a t e elevated t h y r o i d h o r m o n e synthesis a n d action.
W h e n t h e T S H levels are c o m p l e t e l y s u p p r e s s e d ( b e l o w t h e l i m i t of d e t e c t i o n ) p r e c l i n i c a l or o v e r t h y p e r t h y r o i d i s m h a s t o b e
e x c l u d e d b y d e t e r m i n a t i o n of free t h y r o i d
h o r m o n e levels ( F T a n d / o r F T ) . P r e c l i n i c a l
a n d o v e r t h y p e r t h y r o i d i s m has a r e l a t i v e l y
h i g h incidence i n patients w i t h m u l t i n o d u l a r
g o i t e r i n i o d i n e d e f i c i e n t areas.
4
6.2.3
3
RADIOISOTOPIC I M A G I N G
V i s u a l i z a t i o n of i n t r a t h y r o i d a l f u n c t i o n a l
heterogeneities a n d calculation of regional
differences of functional activities i n the
t h y r o i d can o n l y be a c h i e v e d b y r a d i o i s o t o p e
scintiscan [13] a n d c a l c u l a t i o n of t h e u p t a k e
[19,20]. I n n o d u l a r g o i t e r s , t h e t e c h n e t i u m 99m pertechnetate
scintiscan
can
detect
h y p o - a n d n o n - f u n c t i o n i n g n o d u l e s as w e l l
as h y p e r f u n c t i o n i n g h o t n o d u l e s . U n d e r exogenous or spontaneous
TSH-suppressive
conditions,
quantitative
determination/
calculation of the regional t e c h n e t i u m u p take r e p r e s e n t s a m e a s u r e o f t h e a u t o n o m o u s f u n c t i o n a l activity of h o t n o d u l e s
[19,20]. I n c o n t r a s t , t h e d o c u m e n t a t i o n o f
h y p o f u n c t i o n i n g so-called ' c o l d ' n o d u l e s is
i n d e p e n d e n t of the T S H secretion.
T h e r e is c o n s i d e r a b l e v a r i a t i o n i n t h e d i -
a g n o s t i c use o f r a d i o i s o t o p i c i m a g i n g o f t h e
t h y r o i d w o r l d - w i d e . I n euthyroid patients
with
a sonographically solitary n o d u l e ,
r a d i o i s o t o p i c i n v e s t i g a t i o n m a y be o m i t t e d
w h e n m a l i g n a n c y can be e x c l u d e d c y t o l o g i c a l l y . A l s o , i n s o l i t a r y p u r e t h y r o i d cysts t h e
c o n f i r m a t i o n of t h e lack o f i s o t o p e u p t a k e is
n o t needed. I n all other conditions of u n i - or
m u l t i n o d u l a r goiter, the impact of isotopic
i m a g i n g is h i g h w i t h r e s p e c t t o f u r t h e r
diagnostic a n d therapeutic decisions
and
s h o u l d t h e r e f o r e be r e c o m m e n d e d .
I n endemic goitrous regions, the m u l t i n o d u l a r i t y m a y be c a u s e d b y c o l d a n d h o t
n o d u l e s w i t h i n t h e same g l a n d . P a t i e n t s
w i t h t h i s t h y r o i d disease are at r i s k o f
h y p e r t h y r o i d i s m i n the future. Moreover,
t h e r e is n o r e a s o n a b l e f o r m o f m e d i c a l t r e a t m e n t for this situation. I n patients w i t h
s p o r a d i c g o i t e r w i t h o u t defects o f t h y r o i d
h o r m o n e synthesis or action, if m u l t i n o d u l a r i t y is p r e s e n t , s c i n t i s c a n has t o be r e c o m m e n d e d f o r t h e same r e a s o n s . E s p e c i a l l y i n
non-endemic
areas, metastases o f n o n thyroidal malignancy (bronchial, renal and
breast carcinomas), parasitic infections a n d
g r a n u l o m a t o u s diseases h a v e t o be c o n s i d e r e d as t h e causes o f these n o d u l e s .
6.2.4
C Y T O L O G I C A L I N V E S T I G A T I O N BY
FINE NEEDLE A S P I R A T I O N
C y t o l o g i c a l i n v e s t i g a t i o n of smears of fine
n e e d l e a s p i r a t i o n ( F N A ) m a t e r i a l has its
m a i n significance i n patients w i t h solitary
n o d u l e s [9,10]. I n m u l t i n o d u l a r g o i t e r s , t h i s
i n v e s t i g a t i o n s h o u l d be u s e d w h e n o n e o f
t h e n o d u l e s s h o w s r e c e n t g r o w t h o r has a
hypo-echogenic
structure i n
comparison
w i t h t h e n o r m a l t h y r o i d tissue. I t can also be
used s i m p l y to exclude malignancy i n all
n o d u l e s , w h e n s u r g i c a l t r e a t m e n t is r e f u s e d .
I n i n f l a m m a t o r y t h y r o i d diseases, F N A p r o vides the material for the microbiological
i d e n t i f i c a t i o n of any bacterial i n f e c t i o n .
The v a l i d i t y of cytological investigation
depends o n the experience of the person
Treatment
p e r f o r m i n g F N A as w e l l as o n t h e c y t o l o g i s t .
I t m a y reach a p p r o x i m a t e l y 9 0 % s e n s i t i v i t y
i n t h e d o c u m e n t a t i o n of m a l i g n a n c y i n s o l i t ary cold nodules. The result s h o u l d include
a clear d e s c r i p t i o n of t h y r o i d cell m o r p h o l o g y , a n d of a n y v i s i b l e i n f i l t r a t i o n b y l y m p h o o r g r a n u l o c y t e s o r cells o f f o r e i g n o r i g i n .
Classification
according to
Papanicolaou
c r i t e r i a is n o t h e l p f u l because i t does n o t
refer to the t h y r o i d m o r p h o l o g y a n d the
possible different m o r p h o l o g i c a l types of
t h y r o i d cancer.
T h e r e s u l t of c y t o l o g i c a l i n v e s t i g a t i o n c a n
s h o w c l e a r l y b e n i g n or u n e q u i v o c a l l y m a l i g n a n t cells, b u t t h e r e can also be a s u s p i c i o u s
z o n e . M o r e o v e r , t h e i n v e s t i g a t i o n can i n d i cate a f o l l i c u l a r a d e n o m a o f h i g h c e l l u l a r i t y .
T h e c o n s e q u e n c e s of t h e l a t t e r t w o f i n d i n g s
are discussed c o n t r o v e r s i a l l y i n t h e A n g l o A m e r i c a n l i t e r a t u r e [10,21]. I n t h e case o f a
s u s p i c i o u s r e s u l t , b i o p s y can be r e p e a t e d b u t
for f o l l i c u l a r a d e n o m a , c y t o l o g i c a l m e a s u r e s
are u n s u i t a b l e to e x c l u d e a l o w g r a d e f o l l i c u lar c a r c i n o m a . T h e r e f o r e , w e p r e f e r s u r g i c a l
r e m o v a l of t h e n o d u l a r lobe w i t h h i s t o l o g i c a l
classification of the t u m o r .
225
p a t i e n t s . H o a r s e n e s s or v o c a l f a t i g u e requires a laryngeal inspection. D u r i n g preope r a t i v e p r e p a r a t i o n of e v e r y p a t i e n t t h i s
latter i n v e s t i g a t i o n is r e c o m m e n d e d
for
medico-legal reasons.
I n patients w i t h a n o d u l a r goiter a n d an
i n t r a t h o r a c i c m a s s , i d e n t i f i c a t i o n of t h e mass
as t h y r o i d tissue r e q u i r e s r a d i o i o d i n e i m a g i n g a n d is p a r t of t h e p r e o p e r a t i v e i n v e s t i g a t i o n . C o m p u t e r i z e d t o m o g r a p h y is also req u i r e d ; t h i s a l l o w s t h e exact v i s u a l i z a t i o n o f
the anatomical relationship b e t w e e n the i n t r a t h o r a c i c t h y r o i d tissue a n d t h e s u r r o u n d ing structures and the distinction between a
false or t r u e e n d o t h o r a c i c g o i t e r . T h e use o f
i o d i n e c o n t a i n i n g c o n t r a s t m e d i a m u s t be
avoided, otherwise an unexpected malignant
t h y r o i d t u m o r c a n n o t be s u b s e q u e n t l y treated b y r a d i o i o d i n e . I f a v a i l a b l e , M R I m a y be
u s e d i n cases w i t h d i f f i c u l t a n a t o m i c a l i n t e r relationships between the endothoracic goiter a n d t h o r a c i c
structures
( F i g u r e 6.5).
H o w e v e r , i n u n c o m p l i c a t e d situations, the
use o f t h e l a t t e r t w o m e t h o d s seems t o be
inappropriate.
6.3
TREATMENT
6.2.5
APPROPRIATE E V A L U A T I O N OF
LOCAL COMPLICATIONS
6.3.1
In m o s t patients w i t h m u l t i n o d u l a r goiter
c l i n i c a l i n v e s t i g a t i o n gives s u f f i c i e n t i n f o r m a t i o n to e x c l u d e m a j o r local c o m p l i c a t i o n s , b u t , i f s u r g i c a l t r e a t m e n t is c o n s i d e r e d , m o r e i n t e n s i v e e x p l o r a t i o n of t r a c h e a l
a n d v o c a l c o r d f u n c t i o n has to be p e r f o r m e d
[ 9 , 1 3 ] . D i s l o c a t i o n a n d c o m p r e s s i o n of t h e
t r a c h e a can be e x c l u d e d b y s t a n d a r d X - r a y
i n v e s t i g a t i o n o f t h e t h o r a x . Varicosis of t h e
e s o p h a g u s ( F i g u r e 6.4) m a y be d i a g n o s e d b y
c o n t r a s t s t u d i e s . T h i s c o m p l i c a t i o n can b e
e x p e c t e d m a i n l y i n p a t i e n t s w i t h large r e currences. Tracheal compression w i t h f u n c t i o n a l i m p a i r m e n t s h o u l d be i n v e s t i g a t e d b y
measuring the inspiratory and expiratory
a i r w a y resistance, w h i c h can e x c l u d e b r o n c hial obstruction immediately i n dyspnoeic
T h e t r e a t m e n t of n o d u l a r t h y r o i d disease b y
T S H s u p p r e s s i n g doses of T is c o n t r o v e r s i a l
[ 1 0 , 1 2 , 1 3 , 2 1 - 2 4 ] . I t is, h o w e v e r , t h o u g h t to
be a p p r o p r i a t e i n o r d e r to select p a t i e n t s
w h o r e s p o n d to t h i s t r e a t m e n t s u f f i c i e n t l y
f r o m those w h o d o not r e s p o n d , assuming
t h a t t h e latter g r o u p clearly s h o u l d be o p e r ated u p o n f o r t h e i r r e s i s t a n t n o d u l a r g o i t e r
[10]. R e p o r t e d r e s u l t s o f T m e d i c a t i o n r a n g e
f r o m a r e s p o n s e rate o f 55.7% [22] t o a p p r o x i m a t e l y z e r o [21] i n s o l i t a r y n o d u l a r disease.
In o u r o w n investigation of patients w i t h
d i f f u s e e n d e m i c g o i t e r s [23] r e d u c t i o n o f t h e
t o t a l t h y r o i d v o l u m e r e a c h e d 30%. T h e s e
data w e r e c o n f i r m e d b y o t h e r s [ 1 2 ] , b u t
t h e r e is n o s t u d y i n w h i c h n o r m a l i z a t i o n o f
the t h y r o i d v o l u m e a n d t h e d i s a p p e a r a n c e of
MEDICAL TREATMENT
4
4
226
Multinodular
goiter
Figure 6.5 (a) Computerized tomography, axial slice orientation, w i t h o u t contrast agent. The figure
demonstrates a huge mass i n the upper mediastinum. The trachea is laterally displaced and can be
identified as a hypodense structure. Note the calcification i n the central portions of the t u m o r .
Figure 6.5 (b) M R I , T2 weighted sequence, coronal slice orientation: demonstrates a huge mass
w i t h high signal intensity, and some irregularities. The mass displaces the trachea to the right
side and additionally leads to an enormous compression of the brachiocephalic trunk. No infiltration is shown and histology proved this to be a
multinodular goiter w i t h o u t any malignant invasion. (We thank our colleagues of the Klinik and
Poliklinik für Radiologie of the University of
M u n i c h for these t w o figures: 6.5(a)(b).)
n o d u l e s is d o c u m e n t e d c o n v i n c i n g l y . T h u s ,
h o r m o n a l suppressive treatment c a n n o t be
a c c e p t e d as a r e a s o n a b l e l o n g t e r m t r e a t m e n t
for e u t h y r o i d n o d u l a r disease. I n p a t i e n t s
w i t h n o d u l a r disease d u e t o d y s h o r m o g e n e sis or r e d u c e d t h y r o i d h o r m o n e a c t i o n , t h y r o i d h o r m o n e s u p p l e m e n t a t i o n is i n d i c a t e d i n
order to o p t i m i z e the metabolic status. I n
this g r o u p t h y r o i d h o r m o n e treatment m a y
induce
a limited reduction i n
thyroid
v o l u m e , a n d m a y be u s e d t o a v o i d s u r g e r y .
I n a l l o t h e r s i t u a t i o n s , t h y r o i d s u r g e r y is
i n d i c a t e d a n d necessary i f m e c h a n i c a l c o m p l i c a t i o n s are t o be p r e v e n t e d o r h a v e to b e
treated, a n d if the possibility of m a l i g n a n t
n e o p l a s i a has t o be e x c l u d e d .
M o r e recently,
treatment
with
stable
i o d i n e has h a d a renaissance, at least i n
G e r m a n y , a country w i t h endemic goiter
[12,15,25]. T h i s m e t h o d o f t r e a t m e n t is successfully u s e d after e x c l u s i o n o f a u t o n o m y i n
h y p o t h y r o i d n e o n a t e s [25] i n p e r i p u b e r t a l
c h i l d r e n [15] a n d i n y o u n g e r a d u l t s [12] w i t h
diffuse goiters d u e to i o d i n e deficiency.
H o w e v e r , i n these g r o u p s o f p a t i e n t s , w i t h
the exception of the neonates, n o r m a l i z a t i o n
Treatment
of t h y r o i d v o l u m e was rarely reached. Thus,
i o d i n e s u p p l e m e n t a t i o n i n iodine deficiency
i n d u c e d g o i t e r s is n o t a p r o m i s i n g concept
w i t h respect t o n o d u l a r s h r i n k i n g . I t m a y
h o w e v e r be a r e a s o n a b l e w a y t o p r e v e n t
f u r t h e r g r o w t h o f p r e - e x i s t e n t g o i t e r s after
exclusion of f u n c t i o n a l a n d m o r p h o l o g i c a l
complications.
6.3.2
R A D I O I O D I N E TREATMENT
I n p a t i e n t s w i t h r e c u r r e n t g o i t e r or e l d e r l y
p a t i e n t s , r a d i o i o d i n e t r e a t m e n t is a u s e f u l
alternative to reduce goiter v o l u m e signif i c a n t l y [26]. T h e p r e c o n d i t i o n is t h a t t h e
m e c h a n i c a l l y effective p a r t s of t h e e n l a r g e d
g l a n d consist o f f u n c t i o n a l l y active t h y r o i d
tissue w i t h s u f f i c i e n t r a d i o i o d i n e u p t a k e .
T h i s t r e a t m e n t is safe a n d the r e d u c t i o n o f
t h e t h y r o i d v o l u m e is s u f f i c i e n t to i m p r o v e
respiratory obstructive symptoms and dysphagia. H y p o t h y r o i d i s m may result d u r i n g
long term follow-up.
6.3.3
SURGICAL TREATMENT
M e c h a n i c a l c o m p l i c a t i o n s are t h e r e a s o n f o r
surgical treatment of m u l t i n o d u l a r goiter i n
m o r e t h a n 6 0 % of p a t i e n t s i n G e r m a n y ;
a m o n g these, tracheal c o m p r e s s i o n is t h e
m a i n c o m p l i c a t i o n . I n s o m e cases, p a r t s o f
t h y r o i d tissue m a y be i n s e r t e d b e t w e e n
e s o p h a g u s a n d trachea, t h u s i m p r e s s i n g t h e
p a r s m e m b r a n a c e a o f t h e trachea f r o m beh i n d , resulting i n d r y cough and dyspnea.
T h e s i t u a t i o n is d i f f i c u l t t o d i a g n o s e b e f o r e
s u r g i c a l i n t e r v e n t i o n . Patients w i t h d y s p h a gia a n d H o r n e r ' s s y n d r o m e s h o u l d be o p e r ated o n f o r b o t h d i a g n o s t i c a n d t r e a t m e n t
purposes.
I n general, intrathoracic goiters, w i t h or
w i t h o u t mechanical complications, should
be r e m o v e d s u r g i c a l l y because of t h e r i s k o f
s i g n i f i c a n t , p e r h a p s e v e n life t h r e a t e n i n g ,
p r e s s u r e effects d e v e l o p i n g i n the f u t u r e a n d
because m a l i g n a n c y c a n n o t be e x c l u d e d w i t h
certainty.
227
The unequivocal i n d i c a t i o n for t h y r o i d
s u r g e r y is t h e s u s p i c i o n o f m a l i g n a n c y . I n
p a t i e n t s w i t h o n e o r m o r e so-called ' c o l d '
nodules,
especially
those
with
recent
g r o w t h , m a l i g n a n c y has t o be c o n s i d e r e d
e v e n b e f o r e t h e classical signs o f a m a l i g n a n t
t u m o r can be r e c o g n i z e d c l i n i c a l l y . T h e d i s cussion c o n c e r n i n g the m i n i m a l v o l u m e of a
n o d u l a r l e s i o n w h i c h gives rise t o t h e s u s p i c i o n o f a m a l i g n a n t t u m o r seems n o w a d a y s
to be senseless w i t h r e g a r d t o o u r k n o w ledge of p a p i l l a r y t h y r o i d cancers ( C h a p t e r
11).
Suspicion
of m a l i g n a n c y i n small
n o d u l e s arises f r o m t h e c y t o l o g i c a l f i n d i n g s
o n l y . T h e r e p o r t e d p r e v a l e n c e of m a l i g n a n t
tumors of the t h y r o i d depends m a i n l y o n
the p r e s e l e c t i o n o f p a t i e n t s u n d e r g o i n g t h e
e v a l u a t i o n . F o r p a t i e n t s b e l o w 20 y e a r s or
above 60 years o f age, a n d f o r m a l e s , t h e r i s k
of m a l i g n a n c y i n t h y r o i d n o d u l e s is b e l i e v e d
to be i n c r e a s e d w h e n c o l d n o d u l e s c a n be
d i a g n o s e d . O t h e r a u t h o r s [10] d o n o t see a n
increased p r o b a b i l i t y of m a l i g n a n c y w i t h
age, b u t d i f f e r e n t i a t e d c a r c i n o m a s are m o r e
o f t e n o b s e r v e d b e l o w t h e age of 40 y e a r s ,
w h e r e a s t h e p r e v a l e n c e of u n d i f f e r e n t i a t e d
c a r c i n o m a s increases t h e r e a f t e r .
T h e p o s s i b i l i t y o f m a l i g n a n c y is i n c r e a s e d
in h y p o f u n c t i o n i n g solitary t h y r o i d nodules,
especially i n t h o s e w i t h r e d u c e d e c h o g e n e i t y
w h e n compared w i t h the s u r r o u n d i n g t h y r o i d tissue [18], b u t i t has t o be p o i n t e d o u t
t h a t m o s t o f these data r e f e r t o s o l i t a r y
n o d u l e s . Since c o m p a r a b l e i n v e s t i g a t i o n s f o r
m u l t i n o d u l a r g o i t e r s are l a c k i n g , w e p r o p o s e
t h a t d u r i n g t h e i n i t i a l i n v e s t i g a t i o n o f these
conditions u l t r a s o u n d investigation, techn e t i u m s c i n t i s c a n , a n d , i n cases o f c o l d
nodules, F N A w i t h cytological investigation,
s h o u l d be c o m b i n e d t o e x c l u d e or c o n f i r m a
m a l i g n a n t t u m o r w i t h t h e greatest p o s s i b l e
accuracy. I f c y t o l o g i c a l i n v e s t i g a t i o n l e a d s t o
t h e s u s p i c i o n of a f o l l i c u l a r a d e n o m a , s u r g i c al t r e a t m e n t a n d h i s t o l o g i c a l e x c l u s i o n o f a
h i g h l y d i f f e r e n t i a t e d f o l l i c u l a r c a r c i n o m a is
m a n d a t o r y . W h e n m a l i g n a n c y has t h e r e b y
become u n l i k e l y , the decision for surgical
228
Multinodular
goiter
t r e a t m e n t d e p e n d s o n t h e local s y m p t o m s
a n d s o m e t i m e s also o n c o s m e t i c r e a s o n s .
I n m u l t i n o d u l a r goiters, bilateral resection
u s u a l l y has t o be p e r f o r m e d because o f
bilateral n o d u l a r degeneration. I n order to
a v o i d r e c u r r e n c e , i t is r e c o m m e n d e d t h a t a l l
n o d u l e s be resected c o m p l e t e l y [ 2 7 ] . I n large
goiters w i t h p r o n o u n c e d m u l t i n o d u l a r i t y , i t
m a y be d i f f i c u l t to d e f i n e n o r m a l t h y r o i d
tissue i n t r a o p e r a t i v e l y , so t h a t a n e a r t o t a l
t h y r o i d e c t o m y has t o be p e r f o r m e d .
The functional result depends o n the
v o l u m e of residual f u n c t i o n a l l y intact t h y r o i d tissue. I f t h e r e m n a n t has a v o l u m e o f a
n o r m a l s i z e d t h y r o i d g l a n d , e u t h y r o i d i s m is
a possible result, whereas for smaller r e m n a n t s h y p o t h y r o i d i s m has t o be e x p e c t e d .
T h e classical p e r m a n e n t c o m p l i c a t i o n s of
s u r g i c a l t r e a t m e n t of a l l t h y r o i d diseases are
p a l s y of t h 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 n d
h y p o p a r a t h y r o i d i s m . T h e f r e q u e n c y o f these
c o m p l i c a t i o n s d e p e n d s s t r o n g l y o n t h e experience of the surgeon. These complicat i o n s are seen less o f t e n after s u r g e r y f o r
m u l t i n o d u l a r goiter compared w i t h Graves'
disease [28] a n d increase s i g n i f i c a n t l y i n
operations for recurrent goiter [29].
6.3.4 L O N G TERM F O L L O W - U P AFTER
SURGERY A N D R A D I O I O D I N E
A f t e r s u r g i c a l a n d r a d i o i o d i n e t r e a t m e n t of
m u l t i n o d u l a r g o i t e r , t h y r o i d h o r m o n e treatm e n t is necessary f o r t h o s e w h o h a v e o v e r t
or borderline h y p o t h y r o i d i s m . The a p p r o p r i ate s u b s t i t u t i o n dose o f T s h o u l d be c h o s e n
t o n o r m a l i z e basal T S H levels. I f p o s t o p e r a t i v e basal T S H r e m a i n s n o r m a l , i o d i n e s u p p l e m e n t a t i o n of 100 to 2 0 0 / x g p e r d a y
s h o u l d be g i v e n i n r e g i o n s w i t h n u t r i t i o n a l
i o d i n e d e f i c i e n c y [30].
4
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