STABILIZATION OF ENZYMATICALLY POLYMERIZED 2,4 DICHLOROPHENOL IN
m.w.Deiodinase type 1 (Dl) deiodinates thyroxine (T4) at the 5' position to form triiodothyronine (T...
35
Transcript of m.w.Deiodinase type 1 (Dl) deiodinates thyroxine (T4) at the 5' position to form triiodothyronine (T...
" TSH Is ihen reltlstcl. Prolonged sthn-..latlon Wilt\ TAH srso lftcrtctS&$ TSH s,nfh•sls anci tts b#(IActlvHb 'through p osttranslat\Onl( tootliRcatlon.
Pituitary SH is a glycoptoie\n hormone of !81()00 m.w. Jt is co~posed oft"'o 1511
)eptldt sub IAnits., 1:he·,6(·subunit \s nonspecific btcaus• It is als~ pcut-)f'thfee unrelri•cl hormonas 'L·H•-FSH•C',Il) • ~subun\i of1SH \s c:ow\pldaly M 1iHeretntan d con1alns-t-h• \"['(} pccift'c blolr.glcct"Y ac\f"t 1" roid
~IHs o~ the berm one,. grand
,. f!rs"bunl~ must- he combi,,e.t{ wiih
i: ~ t -~ (.;
~
1 )I I ..
~
T4
T3
c;. t<
Stimulate~ cj~ lnhibi;-v
(Minor)
·SCA/)Uft Tl rc,.,rJOUIIE '10·'1 '1'ho hypothnlnmlc-pltuitnry ulnml-thyrold gland axis. 'fh)IISltropln·rolenalng hor• mono (1'/tll) stimulates ~hyrotropln ('l'Sil) relonsa fro:itho pituitary glont.f:i'tSH stimulates T4 ond
~ Jol fO to n 111lnor '.!!!greo '1',, socrctlon by tho thytolr.l !Jiom •. r ~ orising !tom T4 In peripheral tlss,ues or
-~
•;!
. I within tl\t.J'ituitnry ylnnd itsolf blockR tho a !feet of TIUI nnd suppresses 'l'SH releoso by nego.Livo M u ate leedbnci(. ilopomlne ond somntoslntin olso lonicnlly inhibit 'VSH reieose. .
yroid Ctlls.~cortlseat and gr6wih hoonone red\AC'f TSH sec,etion ,'_',:_·,J};.f ptobah\y b~ s1fm\l\ating somntostatin ff'lra-se.. . · . .-L
,t., .
.. .. ...... .. _ ... ~ .... -.............. · ..
:
·.·.·. ;. ;:,:!;:t;~:" > >
Porlvonlrlcular roglon
Small·bodlcc.lncurons In lhc nrcu;~lc nucleus nnd mcdinn eminence " synlhcslzc nnd secrete thy;_olroph~~ •. releasing hormone (TRH>..: . ,. ----.
Colloid .. : ~ :' .
·:· :}·;:_;
FIGURE 48-9. The hypothalamic-pituitary-th)•roic.l :~xis. Small-bodied neurons In the arcuate nucleus and median eminence of the h)•poLhalamus secrete thyrotropin-rcle;~sing hormone (TIU 1), a tripepude thaL reaches the thyrotrophs in the anterior pituitary via the long portal \'eins. TRH binds to a G protein-coupled receptor on the thyrotroph membrane, triggering the DAGIII', pathway, leading to protein phosphurylauon and mising (C., .. ],. These pathways stimulate the thyrotruph~ to symhesizc and release thyrotrophin (or thyroid-stimulating hormone (TSH]), which is a 28-kDa glycoprotein stored in secretory granules. The TSII binLls t<l receptors on the basolateral membmne of th)•roid follicular cells, stimulating Ga .. which in tum activates ad~nylyl cyclase and raises (cAMPI,. As outlined in Figure 48-3, TSH stimulates a number of steps in the synthesis and release ofT, and T,. inside the pituitary, the typc-2 fomt of 5'/3'-monodeiodinase con,•ens T, to T1, which negati\'ely feeds back on the th)'mtrophs as well as on the TRH-sccreting neurons. Somatostatin and dopamine-released by hypothalamic neurons-inhibit TSH release and thus can inOuence the "set point" at which TSH is rele~scd in response to a gi\'cn amoum ofT, in the pituitary. AC. adcnylyl cr.:lasc; ATI', adenosine triphosphate; cAMP, cyclic adenosine monophosphate; DAG, diacylglyccrnl; 11' 1 , inosihtl triphosphate; PKC, protein kinase C; PLC, phosph<>lipase C .
. , . ~" ~
_,.; ·: l'· . ·;~ .
•'. ;.:.<;;~~}.\,;:,~; ,; ·::>h~;,.;: ~- .-:~.r~--~;::j ;:rj~;·;.£i~i~
-)
. , ..
:•;;.:.,./ -·~..:...-~-: ·.f-~ .. . :: .. ·.; .
. _ · ... ;;; ;-.: .. : DNA : -~ ·. >. Cell size · ~ ". _·.·Trapping of r.- .. .":.. · Glucose oxidation .. :'· .. · :; ·: · · ·. · ·. RNA . , ·· . . Cell number ·: : · Iodination · . · NADPH generation
Protein · ' · · . . Follicle formation Coupling . . ·· · .·: · ~":··'. · : · Phospholipid · Endocytosis of
· colloid Proteolysis of
thyroglobulin
~- : ~··
.... . . ..
. . ·.· :~:::.,: :_ . ~· ,. G..Owth .. , ,
. -... : ~·:::-~:~~~-·:.~~-·-.. : :-:· -.; ... . : ·-· . .
.. ~
T . ·.
Synthesis of . hormone .
-~- ... :. ..; .• ..
~~: .. _,,:~~-~-- :_:_:·: ·:< .. ~:~~-; ... :f~::~::r:~~=:~L::?~>.<.}~:-~: :~,-;·:::~:~. :. :> T-Y ': :~--- .-:~: .. _(;·::.:._~- ::·_-- .. <:-.:~ :.~~-:::·_.-:_ -~;~_:·,;,·)~,;:::·:.·.·, __ .;~:·.:::.~}/·,_:<· .· ~- .. :···: .... i:;.
FIGURS 40 .. & TSH actions on the thyroid cell. Cyclic adenosine monophosphate (cAMP) along with calcium ions (Ca + +) and phosphoinositol products act as second messengers generated by TSH binding to its receptor. All steps in thyroid hormone production, as well as many aspects of
:L; . tbyroid cell metabolism and growth, aie stimulated by TSH.
AI . "l· . . . ·-·:; ... '"•
·:: -~·-
. . ·~. ·- ··: ...
-1• ~· ~ •• ·~ •• • - • • .•••• •
TH-YROID ,o·
;.\
.... ·
FUNCTION:
. CUBICAL EPlTHEl_l(JMextracts f~6~ .·· . the_OBI6od str(zam (a_nc;1 eoncenotrates) .-· :·_ 0
•• .... • .... • , •• ·.-~.-- .. .. ... .. •• • • • • •• • .. • • , • .·0 ..... 0 ° • • • • • • 1 0
. · IN.ORGANIC··IODIDE.o . ,0 : 0 ,· :: ,_. 0.0°_ •• • :.:. 0 • t
"·"" " .,,.. . - .. . ... . _ . ') p,y .\ ·. @c·;~~¥ifti e~rr=' (Q ~/;£s!f!!l!!!!i} \\ ..
Sy 1l \la~ks fft(&"man gutotlon1 the tlat\4 ts /~ . 0 ° 0
• • '
apeblf 0 ol synitatsbi,.-go and sectttlnt ibytoi.a hc,t ... -(_/' 0 f'AR~~~~/~LAR
11Cifttt Wtht: •1\• Uhnuh.u oftl\f fftal hypothalaft\ .. S + 0 u.s · 0
, ncf pffotR\iyy~·,,,"d·1'hls tt\t\tt t~ios Is requiltd ~ ul..~ .t, C:"'p~ ~wr.Ro .vovneqM't! ".,.' \p1ffytuint 4evtlopnt•,\ fA.~tt• --- .. :.~iWI&~Of 1nt•1tumct s.t.tc1•P b~ct"'~' t'~itbt~ .
0
0 0
f!-~~:h~one;·~OVIb pif'-''t"~J St~u!a:~'tl9 \loQllotlf. Cct~~ou_t~~~<.!!~c~~···,: .. , ·. ·.·.
I r L ). ':: t r l
~~ \'
Parafollicular cell"' (tR'celi) ~
-Blood
capillary ,...,.-- ~
Red blood. C'ell ..... w.
---
/Thyroid gland
Follicle
FIGURE 48-1. Structure of the thyroid gland. The thyroid gland is located anterior to the cricoid cartilage in the anterior neck. The gland comprises numerous follicles, which are filled with colloid and lined by follicular cells. These follicular cells are responsible for. the trapping of iodine and the synthesis of thyroglobulin, which contains thyroid hormone as part of its primary structure. Th~se cells also secrete thyroglobulin-the major protein of the thyroid colloid-into the lumen of the follicle. The thyroglobulin protein that is stored in the follicular lumen contains numerous iodinated tyrosines and thyronines, which are derivatives of the amino acid tyrosine. On command, the follicular cells take up the thyroglobulin and release the thyroid hormones triiodothyronine (T3) and thyroxine, or tetraiodothyronine (T4), into the blood.
j
f
i I
\ l I
l
____/\_____ . Peroxidase 1 2 +HO~CH2-CHNH2-COOH ~
I . HO-o·CH2-CHNH2-COOH_~ ~·WW• I ft 1'\ in .,,.
Monoiodotyrosine + Diiodotyrosine ~
I I HO-o-O-o-CH2 -CHNH2 - COOH
- I '11'~-= ... =--~-,"'~,.._,."''"~·~:=
3sa!~• illoaoihroiilnErffP ~-~,'ii.~~ .. X~:.¥-·f<.~:~r~~r:t-}.:~;·2·'"'"'/,.:~~---:~I Diiodotyrosine + Diiodotyrosine ~
I I HO-o-O-o-CH2 -CHNH2 - COOH
I .raiotiW~irm~~~Fifl\1 ~li"A~)J:.-:::,:;~?•·~"'.!i.V.i.lu .. .t;.:!t'ii
Diiodotyrosine + Diiodotyrosine-----+
I I HO-o-O-o-CH2 -CHNH2 - COOH
I IEt,~iiii&ffrt~ ._,,·;il~"1.;.;;.4..;i;i
Figure 76-3 Chemistry of thyroxine and triiodothyronine formation.
~ Th)lroi4 hormoneswca uniqt.tt ln ih.tat4ht) lntcwpo-
lrc. an Inorganic elc.tr'&.n~ lc.tline, 11110 an org.1n'1c. rv.t\u~a4t \IP ~huotno\ccc.clt~ c.ftht ami,.oa,icl ro~ii~ At ~cr•t"') pr6duchof.+h• th~raidCJJar.d (~) e l(nc.~rt as iodo'lrlf nine\- ( l'"t1( 1 rfJ '~ .~
I 11 • do . ""\:: CH,yHCOOii
· -·- -·--.. NHl (3)
Tyroalno
I
1 . .rL• ....... , + ' ,_,r· . 'r
'o, o\• •
r-HO . ~ CHfHCOOH
~NI11 OR HO--<' '~ CHlCHCOOH I NHl
I .' 1 \ ~ .
Mono·lodotyro&lno (MIT) ', Dl·lodolyroslno (Din ..
I
I>IT • Olr -• 110-o-O I
I
3,5,3 ,5 ·latra-lodothyronlne (thyroxine or T~) -
OIT • MIT- HO-b-O ! .
,, ..... I ~ I '
CHJyHCOOH
. NHJ
~. :: ,·i,. '
~.·~ ~·.:~; ;: ~ ::; . _: }
·CHzCHCOOH I ·, ., . NH2 : .• ••• • .. ! ; •
i· ',•
• ,I .
. ' ;"I;'! ,.
I 3,5,3 ·lrl·lodothyronlno CTll J : I ! ."1 ( • 1. ·: ~ ' , ' . '•r '· - -.r;,,. ,. ' ..
Tyros ina
HO 0 CH2CHCOOH ~H2 ·,:!i, ; .: '·. ~,,, . ·;·'
I t : i, \; ~:~ I ', ' ' : ! ·: ;' ~ ,· :
CV , 3,3 ,5 -~1-lodothyronlno (rovorse T l) •. , : 1,. , ~ . • 1 ••
. lhe 1n0Jca• profl~ts ~· ·.: , .. :: .... ,,. · ... ! .. •·., •. i,") .~ -tt"tralodo4-hyro,1•ne knoua., asih\lro•ine Dl'e( · · .. ·.·., · :···. i: ·
F1g. 5.3.4 P~h;"Y of th?,-oid hormone synthesis. · · · . ·.:) .. ;.:: 11 1 ·. 1 L ftrrul t• as iq. 1$ UJA\ccufe 1-.tnction.s lorge\y l)Sa · rculo'hng ptt~honrilne~ecretcd In ~tte• lassqt~U1-v ii "3,~,J' .. triludO"thyronit'e1 kl'oWJ:hSimp" a.sifiio-•thyto t"ine af\d rcf'trracl .,, a~ ~~h\s -moletvls 1-»ich ptovides ~WW'»Ity al\fhyroid bonn one aci\vitjf 1U1)&t e.t\1), IS «ctuol~ pto~wced "".1."~ \~ pefiph-•o\ tissues Mfll ike prt\h6rMtbtTat" iri.vlal ~fe-ry pro~et with 110 iclenfiFtetl ~·"•' ae.'tion Is 3 ,i ·•beiol6t\,..6ftine. 1'hu b "nolt'n~ ret~U'St1j orr-r,, hec~s·i~dif'Qr.s{tom1; 61\\J )r :ntion~6rtt of.<\he thrf~ \oditte a-toms :This l~inac+ive.al,.tmn,..e proluc.t-
1hc. J2lohormone. Lt.t· . . ·""'
>
Tnyroxtl'llt ~(11 1 tt.o '111'•tetralodO•I.•thyranl ne1
o-lodlhe 0 _b__hHH Ho- ~ofr{-f-cooH 0 0
I-r NH2
Triiodothyronine i!:i1 (3,5,3 ·,-trllodo-L-thyronlno)
-L ~ H H Ho-0-o-)0>--f-{-cooH ~ H Nl~2
Rcvorso T 3 (rT 3) (3,3 ',5 • triiodothyronine) .. 0 0 H H
HO~o~f-{-'cooH 0 ; H NH2
Peptide backbone of thyroglobulin molecule
~~ ~~i-o HO ~-0 ~-f-f-H
0 0 H~N~
Lnlcr, inside the lysosomcs of the folliculnr cell. enzymes will cleave the two peptide· . · bonds shown, · releasing T4•
Amino acid
FIGURE 48-2. The structure of thyroxine (T4), triiodothyronine (T3),
and reverse T3 (rT3). I. I? and U1 all are products of the eo\lpling of_ two iodinated trosine derivatives. Only T4 and T3 are biologically aedve, and T3 is ar more active than T4 because of a higher affinity for thyroid hormone receptors. Reverse T3 forms as an iodine is removed from' the inner benzyl ring (labeled "/\") o,f T4 : rT 3 is present in approximately equal ·molar amounts with T3• However, rT3 is essentially devoid of biologic activity. As shown in the bottom panel, T4 is part of the peptide backbone of the thyroglobulin molecule, as arc T 3 and rT 3.
Cleavage of the two indicated peptide bonds would release T4 •
.......... J
~:: f·
I ~ 1
\.
Jr\_ )----\__ NH2
HO )=! OV-' CH,-dH-COOH I I
Triiodothyronine (T 3)
-PI -PI NH2
HO 0 fs ' CH2 -C1H-COOH
3 -I I
Jr\_ I'- NH2 HO )=! 0 ~-' CH2 -C
1
H-COOH
I I Thyroxine (T 4) 3,3'-Diiodothyronine
·n I'- .NH,
HO)=JO ~-' CH2 -C
1
H-COOH
I I
01
ReverseT3
I I
HO-o- 0 -P-1- COOH I I
, Tetraiodoacetic acid (tetrac)
FIGURE 32.4 The metabolism of thyroxine. Deiodinase type 1 (Dl) deiodinates thyroxine (T4) at the 5' position to form triiodothyronine (T3), the physiologically active thyroid hormone. Deiodinase type 3 (03) also enzymatically deiodinates some T4 at the 5 position to form the inactive metabolite, reverse T3. T3 and reverse T3 undergo additional deiodinations to 3,3'-diiodothyronine before being excreted. A small amount of T4 is also decarboxylated and deaminated to form the
r· I
HO -o-0 -o-CH, -Cr~ COOH I I
/-
Triiodothyronine (T3) o~·· D Inactivation
a lion
-01 -01
NH2
HO 0 fs ' CH2 -C1H-COOH
3 - -o- -o- NH2
HO _o f_, CH2 -6H-com
I I I I Thyroxine (T 4) 3,3'-Diiodothyronine
~ation . ~ D . h. •/'\_ NH, 01
HO )=/ 0 )=!-' CH2 -c
1
H- COOH
I I
Reverse T3
I I
HO-o-0 -o-~- COOH I I
Tetraiodoacetic acid (tetrac)
FIGURE 32.4 The metabolism of thyroxine. Oeiodinase type I (01) deiodinates thyroxine (T.) at the 5' position to form triiodothyronine (T 3), the physiologically active thyroid hormone. Oeiodinase type 3 (03) also enzymatically deiodinates some T, at the 5 position to form the inactive metabolite, reverse T3• T3 and reverse T 3 undergo additional deiodinations to
- 3,3'-diiodothyronine before being excreted. A small amount of T4 is also decarboxylated and deaminated to form the metabol!te, tetraiodoacetic acid (tetrac). Tetrac may then be deiodinated before being excreted.
.\
l .
l
1~1 NH2 . . .
HOOCH2-c~-cooHtfwomolcc.ulfl~ot(hea'"l"oat\ds)= ~~~h T,.. / Tyrosine '\....
,J.)_ Nr2 H .... • )-11 CH2-CH-COOH
I Monoiodotyrosine (Min
h Nr2 HO~CH2-CH-COOH
I Diiodotyrosine {OITI
(x2)
..l\. K N~2 5'-Monodeiodinase HO .)-11 O--y-CH2-CH-COOH
hh N~2 HO--y-O--y-CH2-CH-COOH
I 1 I I 3,5,3'-Triiodothyronine 3,5,3' ,5',-Tetraiodothyronine
IThyroxine, T4) ti' {T3) 1
)1t1e COV\tent of iodide within 5-Monodeiodinase
'th• -\h'iroid gland is 100 timgs , . 9ttb'ter than ttae amount · I · N~ <~o?•dtd daily· fo!' hormone Hop.o-p-cH,-c~-cooH p roclucHon. 1 I
Afllhis Is .rioted in fhe form ol 3,3',5'-Triiodothyronine : 1odolytosilles and iodo\l\~ronit\e,, (Reverse r
3)
fhe human i.s prc,ie.cied for1, months lrua" tbe eff•cls of iod\de! de{idet',y(appfo~\~8\e.ly). '
Fig. fSO..l. Thvrold honnone svnfhf"_c;t~ ~nrl Qtn1t•hu·- nf"th.,.,..,~ ).,,._.....,. ..... ,.. ....... ~ •'1..-'- -----------0
-,
Figure 76-2 Thyroid cellular mechanisms for iodine transport, thyroxine and triiodothyronine formation, and thyroxine and triiodothyronine release into the blood. DIT, diiodotyrosine; ~t11T, monoiodotyrosine; NIS, sodium-iodide symporter; RT
3, reverse triiodothyronine; T
3, tri
iodothyronine; T 4
, thyroxine; T c• thyroglobulin.
I~ I
NIS ,_
Na+=r:2 I
RT 3
Secretion
I c I o I ·.;:; , ro i c
~~ :0 I
\
T3 I T4 \
\ ''-...
~ ,_ • ~··-· .. 0 >,< )Ia
~ Thyroglobulin § fi~ ~t~~·, precursor (TG) ..... ~oo~~oC.~\"';, ~ ~ l C'j]_~nw-~ 0 ----~~--ll~
't!t/lff?o
ER Golgi
M\:3~ T 4 Proteasesl
----------------~~ Storage of Thyroglobulin. The thyroid gland is
unusual among the endocrine glands in its ability to store large amounts of hormone. After synthesis of the thyroid hormones has run its course, each thyroglobulin molecule contains up to 30 thyroxine molecules and a few triiodothyronine molecules. In this form, the thyroid hormones are stored in the follicles in ~n amount sufficient to supply the body with its normal requirements of thyroid hormones for 2 to 3 months. Therefore, when synthesis of thyroid hormone ceases, the physiologic effects of deficiency are not observed for several months.
MIT DIT T3 RT3 T4
Each 111olecule of thyroglobulin contains about 70 tyrosine amino acids, and they are the major substrates that cotnbine with iodine to forn1 the thyroid horrnoncs. '
, But onlv 4 to_ 8 of these are normally incorporated into thyroid horm?n~~~ ..... ~ - ·• .
,. .. ---~,
Blood
1- ,,,],.J >'<
Na+ :::,,<
2 K+ Ill( :::::= ""<
3Na+ • ........_ , .... -<
T 4 Ill( II:
T3 Secretion
/
FIGURE 32.3 Thyroid hormone synthesis and secretion. (See text for details.) ATPase, adenosine triphosphatase; DIT, diiodotyrosine; ER, endoplasmic reticulum; MIT, monoiodotyrosine; NIS, sodium iodide symporter; T 3,
triiodothyronine; T4, thyroxine; TPO, thyroid peroxidase. Modified fromLarson PR, Davies TF, Schlumberg M-J, Hay ID. Thyroid physiology and diagnostic evaluation of patients with thyroid disorders. In: Larson PR, Kronenberg HM, Melmed S, Polonsky KS, eds. Williams Textbook of Endocrinology. lOth Ed. Philadelphia: Saunders, 2003.
Follicular cell Lumen
lodinatio_n and /MIT --coupling ~ T __ DIT
g--T ' 4 T3
·r
coo-
• I H 3N-C-H
I
¢ OH
conlligam>n: TSH stun ates the conjugation of iodinated tyrosines to Conn T4 and T3 1inked to thyroglobulin.
Trd In : TSH Increases the acliVTiy of n Na/1 colransportcr (NIS) IIIII m ''"'"l"l"l'ollllll'lllht1111C ur tln•thymlli fulliculltr cdl. Tin.• tcH\IIt is inctc.1SCU Iodine lnii'Pillg: the r.>llo or folllcul.u-cclllodinc lo pl.10n1a luulnc (the su-e.> lieu thyn>id/Mcruon <>r T /5 rnlio) incrc.>scs
ndcr conditions of hil:i> TSH.
Iodide leaves the cell probably via pendrin, and enters the lumen. T~ follicular cell also s~ocretcs thyroglobulin. Thyroid peroxidase, on the luminal surface of secretory vesicle, oxidizes 1- to I 0•
I. . >:mr:::»
··.·~.: !·:··· ... ; :._.· ... _
\ IT.l • • *O*CH,
• • H,C
~~CH, • . • H,c) 'oehydro
HO~~CH,· t t: Follicular
I Reverse T3 (rT 3)1 lumen . Blood
FIGURE 48-3. The follicular cell and its role in the synthesis of th~Toxine (T,) and triiodothyronine (T3). The synthesis and release ofT, and T, occurs in se,•en steps. Inside the follicular cell. a deiodinasc convens some of .the T, to T1. Thyrotropin {or thyroid-stimulating hormone (TSHI) stimulates eoch of these steps except step 2. In addition. TSH e>«rts a growth factor or h)·pcrplastic effect on the follicular cells. DIT, diiodot)'<oninc;
LIT, monniodotyroninc.
. ./ ...
(HAPTER 9 ENDDUIIE PHYSIOLOGY 359
r, .:\ --,
Blood Follicular epithelial cell Follicular lumen
I- > <.
oat.·on antl ~up lln9 occur only wi--Lk -! )rc,~in t linked n lubi.A lin.
FIGURE 9-16. Steps Involved In the synthesis of thyroid hormones In thyroid follk:ular cells. Circled numbers correspond to steps discussed In the text. DIT, dllodotyroslne; ER, endoplasmic reuc·ulum; MIT,monolodotyroslne; PTU, propylthiouracil; TG, thyroglobulin; J T3, triiodothyronine; T4, thyroxine.
:j ., ,.'. -:'.i ~ :·
~.,•·""-~ .......... --:.S:.:.L~(f;. • .,-·:.•,:r\"=='~:JJ.~~:-"~~":-c..,;•,.~"!..•~ ... ~~~ . .r:\.~:.o.;.~_..:;., .. ; .. ·.~:-:·~-,~: • .,..·;.r"'""'·~ .... "":.· ... ~-·t.:·- .... ,.-:1 ..... ....... , ...... ,,...~,.,·'l.•·,u., - p.-,. ,,.., ,,. ... ••. • .,v -··· ... .._ ...... '·• · .. . -.,..,:-~· ~ ..,. .. 1,.}, .......... ~ ... ~ ~~ ~":~'f4,(• ·~ ~~ ........ "' ,. .... ';- ........ , ... _. , . • -:-. • ~ -· • '- •.. ... • •· ..• .&. ·~,. "" ..... - • .,.. '4. "'"" . .. .............. 'I..... . · .. . t ;:· ,...;:;.._.:~_.1,.· • ~!··~--:.:".~-.--~::1(;:;, ... ~1;.\·:.~.-r~~-~·.::-..·'~··~·.:;· ..-. .• --; . .-.;. .. ,. .. .; .~ .... -~·~::..::..-~~·~:=-:-1:.;::·~~ -:...;.,.o:.::..:~~..,.;.;.<:·•:~· -.'!'. :~ t'~c.· ·:· .... -.~ -~ ·~·.:-:· ,: ·,, • .-:· -·:: .. . ,...~ ................ ~ ... ·:}'-;!..'~-·-~ .... -._·;::--~~- ~ •:.,•;:-;o:o""+.,r-t'•"; ·.~ ••. ·····~· •• :..··. , ••••••. ~ •• ,. •.•• •··. ·: ,. "~' :"li ...... ·-·-:: , ...... ·-. •·•. -:··· ·' - •·•·· ..... · .. ';.~~~~·J..•~'~) f:.J '.-:;:,._.. "!(:-1J.:.~·'.'I'.!~-~.~-~~;;.;1.;.i:~-~._.:.;~--:-·,..,.·~ .t-:. .. :;:.:~ ·: .-:, f!,:- ···.-.:·, ·,.< .~;r .: ..... ~-.~~:-- ·jo~; •• ;:~::.:~:. .. ,.,'.!...;;~-~ ~-. ;·; ·:::.: ~ '!-_,·."·'·· ·--,·; .. ~·:···· ·•·:· ~:--. ~: •• ··:. • •• •. • .•. ~-~,-~ ••• )!. •• ~ - ........ ~ .• ..,..."-=·:'10' ....... ,."'.,~ ·•'"''"···· , •....•..... ,, , ......... ~ -\ ~ ..•. ~~.---"\ ............ , .. _. .· .... # .
~~1.~~i;~1tfi\~';:~~~~~"iff"~f~: ;:z:::f::Y{'?f:' !'>S•'l~'~;,rt~t ·:.'.;;~:~~;;,.;:x:.:;; =::;;_~;~_;:~?,;:' <~: : : • _: {i/. ··. · . . ':'J·; ·:<.
~~~~~-~':;-~~ ·, •. ·h~ .. i-n ·.-~ ..... "'""1··-~ ~·s:=···- .. " = ---···---- : • .. •.
. I .. ' .· ..
.• . t . II Table 53-1 Thyroid hormone tuqtover
..... .-: ..
: .• .. · ... :,,
. . . : -.~:_;_ -~· . . . . . . . .... . ~- ~ ~ ·:. :.: .. :·<:· :·· ... · :·~_-;:~
T4 T3 rT3 f: (..
: .... ,. ....... ... :-:~ ..
•.
Daily production (J.Lg) . 90 35 35 .~ From thyroid {%) 100 .. · 25 ··--· 5 ~~ FronlT4 (%) - - 75. 9517
.• ·- ... ~--- ....... - .. - - . -
?xtracellular pool (J!g) --~ 850 40 40 Plasma concentration
Total (J.Lg/dl) 8.0 0.12 0.04 .;··
, .... __ ·-Free (ng/dl).-. H-- 2.ti o':'2'8 i 0.20 ;;r· I.
Half-life (days) 7 1 0 .. 8----t/· ·
··•.
Metabolic clearance (I! day) 1 _ ... m.-.. :~~. --· _ . ?? , __ Fractional turnover per day(%) 10 · . 75 ~ 90 _.;.,
·· .. '
~-.. , ... ' ... . _ . .,._ ....... ~ ....... _.·,- .s- .. --~.,:~·-::--·--------:---·-········.···
, ... ·•· . . . .. " .•
. •
. . . . .. ·-~~~:>!~!; ~;:_}~~::<· ·t~=t- ··;·: .. .-"' '· .
.. ;;,. -~ ·'· · .. ·.: .,.
99.5 % is bow1d to TBG (thyroxinbinding globulin).
r:: . .-··· •. < 0 ·-.
.
~-plasma_.·.
99.98% is bound to TBG.
5 '/3' monodeiodinase activity removes the 5'
· iodine, converting T4 to T3•
T4 and T3 enter the cell either by diffusion or by carrier-media ted transport.
·.:·/~~~~!~~~e . , • Na-:K pump .
:, • Gluconeogenic enzymes ·
1, • Respiratory enzymes . . . . . .
~---~. Myosin heavy chain
1 ~ adrenergic receptors
..--.- Many others
FIGURE 48-5. Action of thyroid hormones on target cells. Free extracellular thyroxine (14) and triiodothyronine (T3) enter the target cell either by diffusion or by carrier-mediated transport. Once the T4 is inside the cell, a cytoplasmic 5'/3'-monodeiodinase converts much of the T4 to T3, so that that cytoplasmic levels of T4 and T3 are about equal. Both T4 and T3 enter the nucleus. Thyroid hom1one receptors bind to DNA at thyroid response elements in the promoter region of genes regulated by thyroid hormones. The binding of T3 or T4 to the receptor regulates the transcription of these genes. The receptor preferentially binds T3. T.herefore, of the total thyroid hormone bound to receptor, approximately 90% is T3. The receptor that binds to the DNA is preferentially a heterodimer of the thyroid hormone receptor and· retinoid X receptor. Thyroid hormone promotes the
"
transci'Fplion of genes encoding a wide range of proteins. mRNA, messenger RNA. _,...,.
.;.
~
(
.: .~ < • ,<:~~~)!}i~ii·.~f:\ / . ·- · '~··· .;~~If::!~¥t:ft~;~::t' ~~':.~$~~~\~':• •;;;).:-.~ifi~~~~ · ''}AY;":"{_zr,) -:~ .. '?i , ... ;:::.1 :! ~tr:~~ .,.·•:=.~~·..;.:·4·:. ~::.:~;;to =-if:~ ._..nj '-~,~~~~--~·.1->;--t ~ .t ,·.~..:~ L~-:::.:.-~'~:~~·;;:."f;:;~ . .;~::.~ .::: ' ·.::\_<·: .: .,........ ':·~".c'·•.- ..... -.::, . r.~·• •.... _, .1<¥·:..-•.H r.; (".r-e·.J~·"'-... .,_'t;;&~·~ .. ~14..,.,._ --r~,.r ...... , ..... ,~ ......... -- ·-·.·.·. .;.
~~~ww~~~~i~ -.- ... ::-··_ ...... ;.~ . .... . , : ... ..
.. · · .. :- ;·~-~·~.Total ...... : . ·:.
-.
T4
:- · 100 nmoVI (80 ~gfl)
Tl 1.8 nmoV1 ( 1.2 llg/1).
. >.~'··~.-.-~ =.~.-~---~r:··: '· ·.c(•.: ·:· ;.,~··: _: ·_ •.. -:-:: .
·.· _Percentage .. : . · Absolute · · ' free ~. · .. ·. ·. ·_ : \ ~ : conce-ntration
= ·•·. • ·: · .. · · • free· ·
0.03 ....
0.3
30 pmol/1 {24 ng/1)
5 pmof/1 (0.4 ~gil)
-~ .!
?::~~~~:~=:~J~·~.::·,.,,'· ;.!~:,~--,'·: ··.~ ... ~ .. :-:}·::-·-~·.-:;.~~~~;?f~::~p;-~;~~i~¥.~~~- ,' ~:: .. <!;~i;:.~·~.·:H;• -:· ~--~~~-._._ T ~: 'o ·-:•'" ·""
~Jable 5.3.3 . ·:·Jhyrotd b.9rQ1qne);>t.n9.!D9 pr.q.t~tf1S ···:·:.;;.!!!:~~}:~,:_:;·:_~· ... : ·:,..~"" ·.· ??- -~- ~ . · • · . l:~&i~-S-:<:--~·t.c~~...~.: .. ·...:.-~ . . ;.:: _:.: :· ~ ".:-:..:--::-:. :.;i;J.:,:.,:;.:\~-..i:.;~~~~·~~~~..;~.::e~:;.~ .-.. -:·:;:!~:.:~~ ;.::..-;~: . .;:·~-~.:.::.: .:~·.-.:...~~~-- -::.~ .. -.:-:....l
:-:~,.-:":"=·
~;--::~-:~ • .2 : .. -- .-· .:........~. "..:l~--»--·
Concentration (J.Jmo111) Bi~ding affinity Actual binding T4
(%) Actual binding T3
(%)
: TBG ~ 0.3 Very high 75 75.
·._-<;·=- . • ; . ·.-- ··~ .... :. ::-~;.:.,··.;\·. , .. .,~-- ~ I _. - ~ ...... :~::Aibumm . · 640 · ·· ....... ···: ···~:···Very ow . ·. 10 25
.~~t~rl\.- . s.o : .• :>.;;:jjs:,;·~?~·'.· ,,_,., 15 o _ ~.,., ·. _;r=
. ·-.---!.. < ~) -~ -~
... . -~ -· ...
~7ft~-.:-~:::.:.:::··"" . ·. - .. ··.":. -:. . ;· .-·.·.-. ~. ·. .. . '.- ·.;.'i=i-' .. : .. ·.: . ..;··1~:.--... · .... ':.t~ :- ....... __ c.;.i:~.-.. ...~5;..7~;-:_~ . .. ':·.;. • .. ~"-:.;; .• -;_.
~:·:,TBG =· thyronine~binding globulin; TBPA =thyroxine-binding pre-albumin . '-~"}f ·_ J.%tJ.rr ·.-:· ·· ·;-· · ·.··- ~,· ·· ·; ··.: ·. -~ · .. ;.:_: ·:::\?~. ::~:··r~~ ;,.· .. : __ : ~-~~::~_.;~ · .- ·-~i · Two o\0\og-ic f~ncHoau can be. osct\bl."d '\C> IBG.
T·:-5~ .. ,._ · --A ..... k ... l·-·(re~t\i'\gTcircu\a·tTiffrife-rvorr·~rt'~-' f-t \lt~f~----.--- ·· trs again~\ acut& changes ivt. i"yroid gland {unc.tlon. Even the su·ddev. addHi~Vl to \he. l'lasrnn of ltn entire dcly's th~roid gland output ~ulcf cause on'J' a 10% i.,crtaSt' 1(1 t)'lo tca'tafTtt coocc>ntration. Afitv (e.tnt~V"I ~oft\1e 9land, n WO\Aid. take 1\eay\y 1 Wtttk·for_th4!· p~s-'ma rq.eoncenfta\ion io {a\\ 50%,·, eco d by bintJinq. . Te~ and T-a 113C~ ptevents the.~r Q omtJru\Af" r.tt-,AI-i,.M ..,,.,~ .... ~- .... -·. ---·-··-''
__../
-~'"'!..~~-... ~= .... .,..,. --::,;: ,: .. '. z 'a:---· •." "' - ... ·7- ·--.. '" . ..:.._ .. ~ .... :~:r?""-:"'~':'~~~--':"'~·~~~~-~;,;,f:1;'-.! ·. •· .. · r-:"·"lll':~~=" .-.. - •· ··.: :-· ~···
~J~}Jt~;.s..,3._3·,·<ihYroia_~.oFiji9[l~~~if1~!D-9~PI~.~if1f .. ::)~~-~f~:~:~~~ >= -~~ .·.·?~ -~: ~--- .. -:·· l:~~j~-~-:-,: .. :;;.;,c .. :~.;,. .. ·_~~~.-:: _:~ .•. ··.-':--~·· :.;;;,;~.;.;:.}:r;~-~~~ ~- .. ·~~~~~.:c"l-~~ -...:·:::.!:.i.~~~ :.::,.-.;...:::'""::.;,:-...:.:..~-=-.::.. .:.~·.....:...,_.:._: __ ·E":...:. •• _.:-.:...."
~r-:~~~i -~ . - --· :....:_, ... ;..,. ~ ... !:~ .. ~-~
Concentration (~mol/1) Bir:tding affinity Actual binding T4 (%) Actual binding T3
(%)
:TBG - 0.3 Very high .':;_.:_A.·:.Ib. um·tn '·. : 640 .· ··· . .- ',~.;;, · .::. '' 1 ~:-v· ery' low_. ·, .. .... ::: . .. ·" ... ~ .. : .. --: ·-· ·- . . . . ··-~~-~~-~·-::·:.·:.:: .. : . . .. · --~ ... - .... ::·,._;..-, :~-.. -_ .. ,-._:.:.,._. --~~:~· ... . . ...... . ··- . . ... .. .
75
10
15
·.., _.T~
-·-- r;·. <~~ -~ ·.J
75'
25
0 ,r~TBPA - .· · .. : .. ···.50 ·· _, .. :·.:;_.,=".::: . .-~,,·,Low ·. :····· _,_\ ~
'~;;.;~:"~-~:.;~ ~--- ·. - .. '.'.. . :· -.- ' ·. .. . '.- ·.:. ~:.-:.,~;,:~· ... 4::.t=l·~-.-~ .-... ~> ~-''~-~~:.- .. < .. :~. ~~-. ·-\~' ~::.TBG =·thyronine-binding globulin; TBPA =thyroxine-binding pre-albumin - ,·:·;k:·- · ~ JJ~!±t~r,· .. : ' · · ·· ·:-· · ~.·: .. ~_,·-. -~~-~:'-.·~:-:;._,>:~:··-:::<·~~-~-.}~~·~·:._:__: :-~!~~_0'" : .-~·:~i·-
Tw-o b\o\ogic f~nci\o1u can be. esct\b~(l \~ IBG. __./
· ····:-:::~--l.=i ..... ~hr'JI";;:.-..-.-r:;.~Tctrcula·tTiig-fise-rvorr-·o-rT,., i-t bCJf~·---_--- ·-'"' again s\ acute chang IS in_i"yroid gland .function. Even the S\iddtl'\ addHi~v. to the. l'lasmc!l of ~n entire day's thyroid glL\r\ci output ~culel cause on\J' -a 10% ii,Crtas" f, tho to't af Tc.t cone fntraticn. Afitv fe.rn tl\1 ~I ~oftht 9land
1 ii wo\Aid take 'Y\eav\y 1 wc•k·fcir_fh•· p~s-
"mcl Tq.eoncentra\ion io .fan 5o•A. ~ eco tl by bintJincy · · Te~ and T-a i13C~ ptevents the~r -Qomttru\:a,.. r.tt-rAI-;,. • .,. ..,,..,l .... ~-.-..-·- --·-··-''
': :-~ ·,t _ _ .. _, :·.
~ lt"'l·-,.~'-"'""w~c~ •· ~-..,···
., i 1
I I I . I
I \
I
h·); .. ;'
j.~·~;'lntracellular effects ·I
:•.
':1• . • . . i ~ ; .•
!:I
t Na•, K•·ATPQte
14 T31
I '
V\IVVV tmRNA
. ;.,' .. .l 1 .;; ~~·,,i<··~;_. -~--\~~--~~.i.ifi~~-;~Jl
.... _.:.,:·:~.'~- i"\.i~l-: ~-.t·;~_'; .. :.:.~u;tt.~ .. ''(• ''<'",-;:..· ·;•:.h···l\I,:,'(J,•i(~~ . :·' • ;:·: -,: ::.i=·;;.··" .·---~~<~~ ,~ -:~.·:-?~~ ·~· · ,.-, :r·.i"l'''·nl' •:•:~·1.-!l~.!l'trJ 1-~"'·
• w, I I\~ -~':\; .. ~~ . ;:, .:-··~.r·:~-::~.~~t'.f ·::1 ·: ~~,-~~rJ~-~~-J({t:i-1t·~·:r:i~~~i;~·i18).
··;·;·.· ... ~.'!'i: ~~;(i~(~:~.·~;\~j~~;~tp.\~!~·; . '- .. · · ·'' -·.···~····'l'i''' ':'~'i*•HJAl : ~· '. . . : =··:·:.: -~ :_-·:: :·; .. ~. ~;·._ t·-::.::~ ·"~'-;
• • : •II O:tJ•'-f 1'~ 1 <:.·;-•tf. . .,-l;:ih•r ,·, .··:" .• • · ........ ,t ................. ~ ....... 'l~ r".~·,-4- -~t:\~~
. . ,. ~~"\." t;.··~· ;J· ..... ~- ..... ~ ·"····•·:t~·:i.·t•.,tW''\' ··)l i1t .. ;· ..... ::;~~f:f·\~:,~..:\;,~t\(1
: • • •: , • ···":'' ... "· • • # • .:. ,,-.:~.~ .... ~·. ·,_ r-{1:'•, ... , . . -~- .. ~~;~!:~-:.;~~· ~:i'l'\ ·~·~=:·~~·\'\\1'!1 1
•: -!.••·,.··Lr\· ,,-;:- \\· ; :00 .. •_.:,,-r.~~~.[{H\ . ·• :·1• .. -~~ .... ~;· .. .-:· .• .-.t.J.~---r:=~~~~~-1 \ . . ·' .. ~···! .• :." ;··""' ~-!\:f!·('\~~~ .. ·;,.j·":'i~ -'1'-''··•t,ljj,.,;l
~ ·: ·· · ... · '·'"··:: '·.·~ ::.·:r;•~i "'J.f-f 1 ·~>Proteins forH;b·\~'~l~~~~
. ·growth and ~·~~!·:.=:trt~l~ . r .'\"!'~=-~~::: .~ . : ma~u~~ .!~~-_:;1:!:~.~~J·,I~(f
t RtipiroAo.ry ®z.ynlM
.. · ......... , ·., .......... l,'l)h·· .. ;•h • "- 't,·•·Jo! ;,ul"l .. ,·.r .• ,~·-r , ..... 1.·:
:_ ····:-:;:~f;~:0.e:.}~:;\\i~;:~~~I~1 ;· : !· .~:>-:;';J;-';'·" ~·).f•C~~·~!~:"~~~ ·•
t Otw enzymest· .. :,\t' .. ~,,.l. ''""It::.'• "'~ and prolilint. 1 :;;!~~: .(·~)}:: i\~~~i't::iii 1• ·,."r.,.. t· .• h.,_,(l.'·l flji)_S,.
\.-------------v------------~ ,.·,~:;!·i:f_:.~._;;.:.~~~-~r·t·h~Ji,l~\~·: t 0 consumption .f\J\f'4 t Metabolic_. .. ~, .ul:i.~l.~i~'·!:i;:iH·;~-~~~'5J•~
I l I I
I I I
1·. I •
I I
~~· ·:. :
02
1r t Cordloc output t Ventilation
1:Whole body effects
2 role . .. .. .. : .;:/?~;~:~ .. ;;.~.};~:'i\·~:hK~~~~V
Substrates
lJ t Food intake t Mobilization
of endogenous carbohydrate, protein, fal
t COa t Urea ~ Muscle mass ~ Adipose tissue
'•. I ::~;_h:~ . •.•.); ··' 1
t Thermogenesis . ;:\:
i: .. l_.
o I •i~.i
. ; ... '· ::[~1;
.• , ..-: :r-.}.
FIGURE 40·6 Overall schema of thyroid hormone effects. The upper portion represents intra· i ·: :.! i . cellular actions; the lower portion, whole body effects. . .'· i ·
-r•···.--·~·-
,,;_·: .. · (' ·::::;.
;:·~.:~ • 'C. •
e_:· ..• ;.
.. · .. ......... :
·.
. I
. .. ...
.. -··-·--:-.""'""":-"''-- ............ -.. .....
·.'.·:· ; ·_,_.
. ·l.~
. · ..
,,. · -i~~\~~~/:i:;H:~.; ... . .;:.:, ·::~.:-:{i:\;~·k; · .. : .·. ~ .. :'_,,:·~· ,.~}'/}:."· .
··.·
/
TABLE 32.1 The Physiological Actions of Thyroid Hormones
. Development of CNS
Body growth
Basal energy economyOof · the body ,
· lnterme~_iary metabolism · .
Thyroid~stimulating ho'rmcine (TSH)secretion · • ··. ·
Inhibit nerve cell replication Stimulate growth of nerve cell bodies Stimulate branching of dendrites Stimulate rate of axon myelinization
Stimulate expression of gene for GH -in~--somatotrophs; .. . .
Stimulate ,synthesis of m·any structural and. . . enzymaticproteins ; .·
Promote calcification of bones
·Regulate ba·sal rates of oxidative phosphory~ .lation,_ body heat production; and oxygen. . c6nsurl1ptio'n (thermogenic effect) >.;. ·
Stimulate .synthetic and degradative path-.. · ... ways· of carbohydrate, lipid, and protein · metabolisrh · · · ·
lnhibifTSH secretion by decreasing ·serisitiv- · · it§'of thyrotrbphs to thyrotropin-releasing:. ·hormone (TRH) · ··.·. · · .. · ·· ·
CNS, central nervous system; GH, growth hormone.-: ···,· ...... : lj
.,. ....... ..
~-.. ,
... ~-· .. ..... ,_, . ~ ... · .. \.. . -. ,.-~,. -·-·-····---- . ····- -- . . -.. lrt • . • · .
: ..
Table 13-6 .. ,. -~ .. . ·r ... -r: · . ' !
summary of_ the Effects of Thyroid Hormones
) - Stimulate calorigenesis in most cells 2- Increase cardiac output
Increase rate cf cardiac contractions Increase strength of cardiac contractions
····>~ ~ -Increase oxygenation of blood Increase rate of breathing Increase number of red blood cells in the
circulation J.f ~Effects on carbohydrate 1netaboil\ism
Promote glycogen fo1~n1ation in liver J:";· ,_ ·=' . · 1 Increase glucose uptake into adipose and ·i';' : ..•. .-· ·.J l . . ,~;·l'c;... .• . . . i muse e ,.,. '. •. . • l I-ok~ hfi;,~~-·-~-:·~·· ~-·~_:_·: : ·. : j ~
~~;:·:;:~>:.:: ·i __ :-.·, · t ;-,. Effects on lipid turnover ~:~:~:-:,::::-~:·~~-- :: .. :! Increased lipid synthesis ~\~,r~;~~~?;: .. :\Jj Increased lipid n1obilization ii-~·!i';i··········· .. -... ~..!T:~~ ... -~-$-~~ ~~ ;. . • • • •
~¢~:~f?r~:'~·, __ :···J Increased hptd oxtdahon .~fL~'t·;: · .·. ·16- Effects on protein metabolism ~-~)f..(~. :i;.,- . . !
f{~f)~~: · ;. _. .j Stin1ulate protein synthesis ·. ·_ · · ·· ~ 1 - Promote normal growth ~ I ·... :j Sthnulate growth hormone (GH) secretion
I ....
Protnote bone growth Pron1ote IGF-1 production by liver
it- Pron1ote developtnent and n1aturation of I nervous systen1 ·
Protnote neural branching Pron1ote tnvelinization of nerves J .
. ...•. :, ............. .
.,.
:.<~ i ·.·~·.:·~--~::.:.~. :··:·.~· ·'. :~··-'-·:~_;i
. ~· ~;· \<l;i;? .. :·· ....... ...... ·
• ".'· I : ~ •:
·.. .. .. ··,· .·· .. ,_ ..
. • · ..
I
I· !! ~~
i .. \~
; ·. ,,.·.; •"-..:."'.
. ·-~:;;--.... --·-r· TABLE 9-8. Factors Affecting Thyroid
Hormone Secretion
Stimulatory Factors
TSH Thyroid-stimulating
immunoglobulins Increased TBG levels
(e.g., pregnancy)
c
Inhibitory Factors
I- deficiency Deiodinase deficiency Excessive I- intake (Wolff-Chaikoff
effec~)
Perchlorate; thiocyanate (inhibit .Ipump)
Propylthiouracil (inhibits peroxidase enzyme)
Decreased TB,G levels (e.g., liver disease)
r·-1 i
·J
''fli :l
-::~
;.~ .~q ;.:~
':l ·::-~
':iii·
~~: ·::-
~~ ' \::
;
,•
+30
+20
+10 .ru ~ .2 0 .8 g ~-10
(ij
~-20
-30
•
-45+-----------~~--------~----------~ 0 100 200 300
Thyroid hormones (J.t.g/day) Figure 76-5. Approximate relationship of thyroid hormone (T 4 and T 3)
daily rate of secretion to the basal metabolic rate. . . . ··-~-----... ~ ........ -.-------~·-~-..........._---- -------. . ....... --~-- . -----~-
. -- . . ---···-.. ---·-L Effect on Basal Metabolic Rate. Because thyroid hor-
mone increases metabolism in. almost all cells of the body,·. . excessive quantities of the hormone .can occasionally in· crease the basal metabolic rate to as much as 60 to 100 per cent above normal. On the· other hand, when no thyroid hormone is produced, the basal metabolic rate falls almost to half normal; that is, the basal metabolic rate be-
_comes -30to -60, as discussed in Chapter72. Figure 76--5 shows the approximate relationship between·the daily sup• ply of thyroid hormones arid the basal metabolic rate. Extreme amounts of the hormones are required to cause very high basal metabolic rates.
· ------.. ··----..--........... ._.,... ... ~-~-~"":w'JII'.7t~-~~---·- .,.,. •. ~~O~'~>;!I!~~-=~·~:"':~~w;~~::":"':''''~~o::-:-"':"1"7-:-"<:"""~~~r.•":-:~~':;a::~<:r:'"='~-... -."":-:"~-o:.•<~·:c·~""''<:"'.:"_, ... _c::"~;"
* Multiple«> hormones, including growth ho<£mone (GHJ,insu&n - like gro~ factors (IGF-IQ)and -II), insulin, thyroid hormones, glucocorticoidsl andr~ens & est~gens contribute to the growth process in humans. Among these , GH & IGF-I have been implicated as the major determinants of growth in normal postuterine life.
* Thyroid hormones are essential in normal amounts for growth; excess does not produce overgrowth as with GH, but causes increase catabolism of proteins & other nutrients.
* Thyroxine at normal concentrations has permissive effect on the action of GH on protein synthesis in its absence aminoacids uptake & protin synthesis are not much stimulated.
* Reduced thyroid activity in eliildhood produces dwarfs who are mentally retarded, whereas reduced GH in childhood produces dwarfs with normal intelligence.
.<:::
{i.f- ~Ultiple Flormones, inClUding gro;&hh~nr;:;;.~U{GHkig~~lin-li~rowth f1t c::: ~or~ (~ l and -ll~nsulin, t_!lyroid hon\J.ones, glucocortico~s, naroge :z:: 1s, an;=strogens contribute to the growth ;;rocess m humans. Among ·rn.. ~ se, GH and IGF-l have been implicated as the major, determinants of gr S:? vAA- in normal pQsnuerine lifeJ) However, deficiencies· (or exc::esses) of ea. <==-= b of the other hormones can ·seriously affect the normal growth of the m -..__=-._ sculoskeletal system as well as the growth and maturation of other tis • ;; ues.
·_·_:.;. ·'·.
-~-!- -'":··'fl.·.· ... '· !,('_~ .; • ' •
~-"-;( .. ~ ... ,
· .. : .. ........... ~ ... ~ V:~
UNDERACTIVITY of THYROID If the THYROID shows atrophy of its secretory cells or is inadequately
stimulated by the Anbzrior Pituitary:- ~
FALL (orabsenor:) LESS (or no) ofTHYROID THYROID
,'HORMONES\ HORMONES\ ' in blood \ 1 enter blood , • ' • to dczerass ' : ~ : .activaty of ~ I ' .-lt I ANTERIOR I I U).' PITUITARY 1
\ ttTS1~tTSH .t \ L~Sl.lff!C{j'~n,/ ,' ~
, t'UJ!.!-~spcml · ,' ~ ', ttJ 11[}!!JgJ!)-------~ .... ~If' &xty
.......... ~$T/MUJAIIHG NOIIMONE 7iSs-u~s
..
Insufficient HORMONAL SECRETION released to Blood Stream.
-TISSUE OXIDATIONS are depressed. irz. Rattz at; which ails use energy is rrzduc~. ' . · ·
~The Basal Metabolic Ratcz falls. .. - Lll.SS H~t is producrzd. .
j;~t~,-;.j MY • , • r;1 ')~,~~-:, • ··l ~'t~
-Body T~mparaturrz falls ~d pczraon . f~rzls COLD). .
Energy units area stored with.watcr • '""e;s ~SKIN- Thick.leat~ry. puffy .. yellow
'\,: .. _--_·,::r-5.'"~- .. :·:j ...... ~ ... !_( .. ~l)t-:t. -~~ .. ·
~'\K. ~ht, ... :',~.:
~{f ~r~·.,.
I .'l;;. ~~~;'.• :,· • :!~, .. : .. ·_.,:-., .. :r·., .. ''i-' .. ~=Wi--~· .. : . 1'\;;::.; .rp_:.; ., -.. ,: ..
t.;~t·;·;:~{~t r~·.:··:·
., ~P., $!<}..'!..... (due to circulating carot:ena:). p,ott,Jsit~0,1
... "" Blood chola&bzrol lncr~ses . tl!eD;...'' Appetite is ~uced; ~eight incr.cza~~s.
SLOWING UP Gutmovements slugglsh ... Qm5tapataon •. OF ALL Heart and Respirator~· Rates and , BODILY Blood P~ssunz-NZduced.
PROCESSES Thought processes slow down_. '· . -Lcithargy; 4pat~; S~mnolence.. .
. ' HAIR- Brittle, ~parse, dry. ,J
· -Slow, husl<y Vo1u. Bone marrow In thtz CNILD -eg e»n~;t.-/41./:ssrzncrz ol - · ' supprczssad-ANAEMIA.
! ~ die glti!lnd -i FAILURE · CRETIN ~ GROSS j of
. - ~ DWARFtNG SKLIETAL . SEXVAL GROWTH .snd
MENTAL } DEVELOPMENT
All "milestones" of b86yhoocl arvz · drz/aytZd.
~~~: i'.\'iV·t,·,·.·. · . · · ~ :.~-~~~:~·{~V.-:;· :] -!:1} '~~'-'\:';\·:\' f, "' .
l~~~~~1J::~·:·\.. . ... ~'!_~R~~~'!~ .(~~tZn oy mou:h) rgstorrzs Jn~~·~~':Ju~-~s .~ n,m.;~!:,
ll!~:f{~;f:~~~:\,.:: ' : "' .· . . . . .. · ~1\ ..... t, ....... t t .......... \ •• '".,
II·~ ~~[l}~t:. } . . . .. ~ .. . .··-· ;_ ·.. ..:.
:··. ·,· .. ·····.·
. }.': ,.
364 PHYSIOLOGY
r
Symptoms
Causes
TSH levels
Treatment
~~-----
--··- - -.. --···--- ---~ .
·')
TA BtE 9-9. Pathoy>hysjolo!fv of Th:•rojd HormnrH~s
Hyperthyroidism
Increased basal metabolic rate (BMR) Weight Joss Negative nitrogen balance Increased heat production Sweating Increased cardiac output Dyspnea (shortness of breath) Tremor, muscle weakness EXophtfi-1 -Goiter
Graves' disease (increased thyroid-stimulating immunoglobulins)
Thyroid neoplasm Excess TSH secretion Exogenous TJ or T4
Decreased (feedback Inhibition of T 3 on the anterior lobe)
Propylthiouracil (inhibits peroxidase enzyme and thyroid hormone synthesis)
Thyroidectomy 1311 (destroys thyroid) ~-Adrenergic blocking agents (adjunct therapy)
•. • ........ ""'"•·.;• ... "'f.i'~ ... .FI-....... ._.\ •
Hypothyroidism
Decreased basal metabolic rate Weight gain Positive nitrogen balance Decreasecl heat production ·Cold senSitivity Decreased cardiac output Hypoventilation Lethargy, mental slowness .Drooping eyelids Myxede)na Growth retardation Mental retardation (perinatal) Goiter
Thyroiditis (autoimmune or Hashimoto's thyroiditis}
Surgery for hyperthyroidism I- deficiency Congenital (cretinism) Decreased TRH or TSH
Increased (by negative feedback if primary defect is in thyroid gland)
Decreased (if defect is in hypothalamus or anterior pituitary)
Thyroid hormone replacement therapy
364 PHYSIOLOGY
r
Symptoms
Causes
TSH levels
Treatment
===' _L.:__ -- . - -
--··- --·· --·----- ··-·--J
-')
TA BtE 9-9. Pathophysjolo~v of Th:rrofd Hormo:nPs
Hyperthyroidism
Increased basal metabolic rate (BMR) Weight loss Negative nitrogen balance Increased heat production Sweating Increased cardiac output Dyspnea (shortness of breath) Tremor, muscle weakness 'EXophth I ~Goiter
Graves' disease (increased thyroid-stimulating Immunoglobulins)
Thyroid neoplasm Excess TSH secretion Exogenous T3 or T4
Decreased (feedback Inhibition of T3 on the anterior lobe)
Propylthiouracil (inhibits peroxidase enzyme and thyroid hormone synthesis)
Thyroidectomy 1311 (destroys thyroid) 13-Adrenergic blocking agents (adjunct therapy)
~ '~."l,"''rl·> .. ;•.:.r-..o·~1'1 ............ , .•
Hypothyroidism
Decreased basal metabolic rate Weight gain Positive nitrogen balance Decreaseq heat production ·Cold sensitivity Decreased cardiac output Hypoventilatlon Lethargy, mental slowness Drooping eyelids . Myxedema Growth retardation Mental retardation (perinatal) Goiter
Thyroiditis (autoimmune or Hashimoto's thyroiditis)
Surgery for hyperthyroidism I- deficiency Congenital (cretinism) Decreased TRH or TSH
Increased (by negative feedback if primary defect Is in thyroid gland)
Decreased (if defect is in hypothalamus or anterior pituitary)
Thyroid hormone replacement ttierapy
~lt~!J(f~~Qi:t;~f1i{1ff~~1¥§g1~f~tli8i£~~~1;;EEILc"-c""4:--·-_'::'fif~J1;· .. ~ I . . . . . .. . ..
Epithelial cells 7\ -"' Capirlaries · . :; ·:· .. ·.
Normal thyroid follicles
Stimulated hyperplastic
thyroid follicles
Collo~d undergoing resorption
Basal membrane
Apical membrane
Stored hormone r.-.,-. rr--- (colloid)
"'-
FIGURE 40-1 Schematic representation of the basic thyroid unit. A normal follicle consists of a central core of colloid material surrounded by a single layer of cuboidal cells~When stimulated by . thyro·tropin, the cells elongate and the central core becomes scalloped because of resorption of the colloid. L·""'~---
~,-,,·~~,._ ................... .
---;:c~; :~¥:;@::{;<-,: :·--
:• ··.• ......
0 ~- ..
"'
TABLE 15-51 Types of Thyroid Dysfunctions _ . c:: .'~x-: ~~i,:.::;;a;~~~;~-::.~-~~Jj._~~-..:;.;:;:: ·~ .. · ... ~:~;;;s:-;;:;;;-:..~~ _.;:.~::: :·::-:.:::.:.~ ... ·;: . .. ~ .. ~:..:;~.:.~~·-t:-'{}.:~::::;::;.:-. ;.::_t;L~~~.-t~!}i~~-~;.:rEi::~~ . ~~a~:u.~:~~~fa:~.1i·z.·.~.::.;::~·::;~::~ ·:~· .... -::.=,· 2j:~-:~:::·,};-;f.tE~;~··.-.::·.~.:. ..-:: .. ·~-~ ~- :· I
·.THYROID· DYSFUNCTION
Hypothyroidism
Hyperd'tyroidism
P~MA CONCENTRATIONS CAUSI ___ _;;;._:;..;;;..;;..;;__ ______ ..__;__O~F. RELEVANT HORMONES
Primary failure of thyroid gland
Secondary to hypothalamic or anterior pituitary failure
L:ick of dietary iodine
Abnormal presence of thyrord-stimulating immunoglobulin (TSI) (Grave's disease)
Seconoary to excess hyp~a:lamic or anterior pituita!J secretion
Hypers.ecreting thyroid tumor
l T3 ai,dT4;f ISH
~ I 3 and T4; ~ TRH and/or ~ ISH
~ T3 and I 4; f ISH
f I 3 and I 4; ~ ISH
f I 3 a.-.d .T 4; f IRH and/or f ISH
fT3 and T4; ~ TSH
-··GOITER PRESENT?
No
G) ® <9
No
j
...-
.... ·.,., ........... , •· .. ....:~~.~···· .. ~ ..
~-....:.--------~--"~--·------····--
-,~_;: "-·_A-.-~
Sllnton IIVlnoou
[Excpbthalmos -(protrusion o_f eyeballs) may be due to 'tri action of an antibody against~ prote~. of the extraocular mus,..les and the connective tissue behind the eye which causes these tissues to swell. It is ·not due to ari excess of thyrcid hormones.] . . . . . ' -. . ~ . . . . ·- ..... . .
Surgical removal of part or all of the overactive gland or destruction by radioactiv~ iodine reduces the thyroid activity.
E'Xo~btba!ID~'-Most, but nu\ all, person) wi'\11 hyper-thyrol~nn de.,e(ap s1me d~.9''' crf prCitrus'ton o.f:itat eye- . ball~ A ynajof dtsrte of t)lophthalmo.s occur.s inaboutontt~ird.o.f'hypert~yroidpatleni.s a1ndthecondiiio11 ~oYY~ftirPcs beconJ•s sevt.re t1\~U.!httt.1f the tyeballf)'tttNsioW\ she1e.,•~ the opi• c V\trva eno\l9h -\6 t!am69t Vtsfo')1.
~
