Cholestasis & Jaundice 2004-1

8/9/2019 Cholestasis & Jaundice 2004-1

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THE BILIARY TREE ANDCHOLESTASIS

Richard Hinton

School of Biological SciencesUniversit of S!rre


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Cholestasis and "a!ndice

# Cholestasis $eans cessation of %ile flo&# "a!ndice $eans ello& staining of tiss!es

es'eciall the &hites of the e es in h!$ansand the ears in rats and $ice nor$all d!eto e(cessive a$o!nts of %ilir!%in

# Cholestasis nor$all res!lts in )a!ndice*# "a!ndice does not necessaril $ean there is

cholestasis


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T 'es of "a!ndice

+rehe'atic The rate of for$ation of %ilir!%in greaterthan the ca'acit for re$oval* Nor$all

associated &ith he$ol sis*# He'atic a, Da$age to liver cells sto' con)!gation

and-or e(cretion* Associated &ith severehe'atocell!lar da$age %, .ail!re to for$ %ile c, Refl!( of %ile %et&een he'atoc tes

# +osthe'atic a, Da$age to intrahe'atic %ile d!cts %, O%str!ction of intra or/ $ore !s!alle(trahe'atic %ile d!cts


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S'oradic Dr!g0ind!ced Cholestasis

In H!$ans# A considera%le n!$%er of ne&l 0develo'ed dr!gca!se cholestasis in a s$all 'ro'ortion of 'atients*

# This condition cannot %e re'rod!ced in e('eri$ental

ani$als*# Effects can %e 1!ite $ar2ed %!t are generall

reversi%le# In so$e cases it see$s li2el that an i$$!nological

$echanis$ is involved/ in other cases it is clear it isnot*

# The res!lt $a %e &ithdra&al of the license res!ltingin enor$o!s financial loss*


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Diagnosis Of Cholestasis# 3, "a!ndice associated &ith an increase in con)!gated

%ilir!%in* 4In 'rehe'atic )a!ndice or liver da$age )a!ndice is associated &ith !ncon)!gated %ilir!%in,

# 5, Raised ser!$ al2aline 'hos'hatase and 670n!cleotidase* In $an ga$$a0gl!ta$ l trans'e'tidaseis a !sef!l $ar2er %!t generall oversensitive/ in ratssecretor IgA is the $ost sensitive $ar2ed availa%le

# 8, Loss of a%ilit to clear dr!gs nor$all e(creted inthe %ile*# NB There are no distinctive 'athological changes

co$$on to all t 'es of cholestasis*


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The %iliar tree 9 a re$inder

# Bile is for$ed % secretion into %ile canalic!li* These ares$all channels %et&een he'atoc tes &hich are delineated % tight )!nctions &hich 'revent $aterial discharged intothe %ile fro$ lea2ing %ac2 %et&een the he'atoc!tes* Thecentrilo%!lar end of %ile canalic!li is :%lind;

# Enlarge$ent of the %ile canalic!li is li$ited % a :corset;of actin $icrofila$ents* This forces the ne&l $ade %ileto flo& do&n the %ile canalic!li to&ards the 'eri'ortal


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Contin!ed# =hile each %ranch of the 'ortal tree generall contains one

'ortal ven!le and one he'atic arteriole there $a %e $an %iled!ct!les of var ing si


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Co$'osition of Bile

#The 'rinci'le co$'onents of h!$an %ile are>0

# 3, Bile salts 4?@ ,* These are strong detergents &hoserole is to e$!lsif fat in the intestine*

# 5, +hos'holi'ids 455 ,# 8, Cholesterol 4 ,# , +roteins 4 *6,#

6, Bilir!%in and other con)!gates 5

# In addition %ile contains the nor$al inorganicco$'onents of e(tracell!lar fl!ids and is enriched in

%icar%onate/ giving it a slightl al2aline 'H*


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Trans'orters involved in %iliare(creetion


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U'ta2e of %ile acids and Salts

# Entr of the %ile salts into the he'atoc tes is largel$ediated t&o carriers/ one an organic acid -sodi!$ co0trans'orters 4NTC+s,* This $oves %ile salts !' theirconcentration gradient 4no AT+ h drol sis is involved, %!tthe la&s of ther$od na$ics are 'reserved as sodi!$ is$oved do&n its concentration gradient* NB This 'rocess onthe concentration of sodi!$ in the cell re$aining lo&* Thisis d!e to the action of the AT+0'o&ered Na- e(changecarrier* To(ins s!ch as o!a%ain &hich inhi%it this ca!se

cholestasis*# The second gro!' of s ste$s/ the organic anion trans'ort

'roteins 4OAT+s, are sodi!$ inde'endent and $!lti0s'ecific* Again the a''ear to %e co0trans'orters $oving

JSH and %icar%onate ions o!t of the cell


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ove$ent of %ile salts into the canalic!li

The final trans'ort into %ile are :'!$'s; &hich !tili


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Transfer of &ater and 'las$a co$'onents=ater and lo& $olec!lar &eight ne!tral co$'one$ts of 'las$a

enter %ile % flo&ing %et&een cells 4the 'aracell!lar 'ath&a ,** The $ain os$otic attractants are the

%ile acid and %ile salts &hich areres'onsi%le for the :%ile acid0de'endent; %ile flo&* Therelativel s$all %ile acidinde'endent flo& is tho!ght tode'end $ainl on the e(cretion ofgl!tathione* Both these 'rocesses

re1!ire sieving across the tight )!nctions so that altho!gh the lo&$olec!lar &eight co$'onents of

'las$a enter %ile readil / 'las$a 'roteins onl 'ass in s$all 1!antitiesand the rate of 'assage is inversel


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Contin!ed# +hos'holi'id/ cholesterol and en< $es The detergent action of %ile e(tracts 'hos'holi'ids and

so$e cholesterol fro$ the 'las$a $e$%ranes of thehe'atoc tes lining the %ile canalic!l!s* So$e 'las$a

$e$%rane en< $es are e(tracted at the sa$e ti$e*Re'lenish$ent of the 'hos'holi'id see$s to %e % theaction of DR8 4ABCB ,

# Bilir!%in gl!c!ronides and other con)!gates

DR3 4ABCB3, $ediates the e(cretion of h dro'ho%ic/$ostl cationic/ $eta%olites* DR5 4ABCC5, $ediatesthe e(cretion of anionic con)!gates incl!ding %ilir!%inand d es* Yet others 4eg ABCJ6 and JG, trans'ort

steroids


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Entr % Transc tosis# aterial can also %e $oved

fro$ the sin!soidal to the %ile canalic!lar face of thecell % transc tosis &hichis/ for e(a$'le/ 2no&n to %ethe $echanis$ for

trans'orting I$$!no0glo%!lin A 4IgA, fro$ 'las$a to %ilein certains'ecies +ro%a%l its $osti$'ortant role is to $ove

'las$a $e$%rane 'roteinsfro$ the sin!soidal to the %ile canalic!lar face of thecell* As sho&n in thediagra$ the 'rocessinvolves


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odification of Bile AfterSecretion

# 3, So$e &ater and n!trients are resor%ed fro$ the %ile d!ct into the %lood vessels &hich for$ the 'eri%iliar 'le(!s

# 5, In so$e s'ecies the %ile d!ct lining cellssecrete a %icar%onate0rich fl!id !nder the controlof the hor$one secretin*

# 8, In s'ecies &hich 'ossess a gall %ladder there is$ar2ed concentration of the %ile % a $echanis$&hich rese$%les co!nter0c!rrent resor%tion in theloo' of Henle*


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Develo'$ent of Cholestasis

# This this $a veassociated &ith

3, .ail!re to secrete %ile acids and %ile salts 0 these arethe 'rinci'al &ater attractants and in their a%sence %ile&ill not flo&

5, O%str!ction of the intrahe'atic %ile d!cts/ !s!all d!eto infla$$ation 4cholangitis,* It has %een s!ggestedthat so$e cases %ile $a refl!( thro!gh tight )!nctions

%et&een he'atoc tes*


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+ossi%le e(a$'les

D0RINJ ETABOLITES O. OESTROJENS

# Action i$$ediate and reversi%le# Clear0c!t dose res'onse# Co$'ete &ith ta!rocholate for %inding site on

'las$a $e$%rane# +ro%a%l 'ert!r%s %ile acid $eta%olis$


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+henothia


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Other Agents Ca!sing

Cholestasis in Ani$als# Lithocholic acid 0 actioncan %e reversed % cholic

acid s!ggesting a co$'etition for trans'ort 'roteins

# O!a%ain Bloc2s Na- '!$'# +halloidin and C tochalasin B* Both affect actin

$icrofila$ents 0 'ossi%l disr!'ting the actin

corset aro!nd the %ile canalic!l!s# C clos'orin A Ca!ses s $'to$s of )a!ndice &ithno changes in the liver* +ro%a%l affects %ile acid$eta%olis$


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To(ic da$age to %ile d!ct lining cells# Ti$e co!rse after treat$ent &ith al'ha na'hth l0

isothioc anate =hen this is ad$inistered to rats at 8FF$g-2g there is the follo&ing ti$e co!rse of events>0

# h Bile d!ct dilation/ loss of $icrovilli/ tight )!nctions

o'en# ?h Si$ilar %!t $ore 'rono!nced/ dilation of er andn!clear $e$%rane of BDLCs* So$e 'ortal oede$a*

# Gh Da$aged %ile d!cts/ cells e(foliating into d!ct*

# 5 h Al$ost total destr!ction of %ile d!cts* .ocalnecrosis in the 'arench $a

# Gh on Regeneration leading to co$'lete re'air


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echanis$s and I$'lications

# ANIT treat$ent affects onl the $iddle and largesi


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Chronic Da$age to Bile D!cts

# This $a %e seen %oth as a res!lt of che$icals &hichaffect the %ile d!ct lining cells and as a s'ontaneo!slesion in aging rats/ 'ro%a%l associated &ith a viralinfection

# Chronic treat$ent &ith ANIT res!lts in3, At 8 da s there is ac!te da$age to %ile d!cts5, B 3F da s there is 'roliferation of %ile d!cts

s!rro!nded % highl vasc!larised loose connective

tiss!e8, B 53 da s there is 'roliferation of %ile d!cts &hich are

no& s!rro!nded % $at!re connective tiss!e# The final a''earance of the s'ontaneo!s lesion is the

sa$e as the ind!ced one


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Bile D!ct +roliferationT&o t 'es $a %e 'resent

3, S$all fingers of cells '!sh o!t into the s!rro!nding 'arench $a* In so$e cases the cells a''ear to %e

arranged in d!ct0li2e str!ct!res/ in other cases not*This &as associated &ith carcinogenesis %!t is $ore 'ro%a%l e('lained as re'air % re0differentiation* The 'roliferating cells are ter$ed oval cells

5, As 'revio!sl descri%ed/ 'ortal tracts enlarge and arefilled &ith large n!$%ers of d!cts &hich do not invadethe 'arench $a* There is no association %et&een thisand cancer


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Cholangiocarcino$a# Liver t!$o!rs $a have $or'hologies si$ilar to

he'atoc tes or d!cts/ the latter are ter$ed cholangio$asis %enign/ cholangiocarcino$a if $alignant

# In so$e cases 4eg co!$arin, cholangio$a is associated&ith %ile d!ct 'roliferation/ in others 4eg DAB 0di$eth l a$inoa

Cholestasis & Jaundice 2004-1

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