REVIEW

Pregnancy and the biliary system

H EL(,A Wrrr. MD, FRCPC, J jOSEPII CONNON, MD, FRCP(LOND), FRCPC

ABSTRACT: Alterations in the synthesis and secretion of bile salts and cholesterol and m gallbladder function occur during pregnancy. These changes are related to the effects of estrogen and progesterone. Biliary cholesterol satura­tion and the chol ic acid/chenodeoxycholic acid ratio increase. Progesterone also Jiminishes gallbladder contractility and emptying. Gallstones occur in 2.5 to 11 % of pregnant women and are associated with cholecystitis in 0.008 to 0.1 % of pregnant women. Operative treatment should be deferred if possible until after delivery; fa iling that, surgery is best done in the second trimester. Endoscopic pap1llotomy may prove to be the best therapy for cholcdocholithiasis. Can J Gastroenterol 1990;4(~):209-214

Key Words: Biliary tract, Gallstones, Pathophysiology, Pregnancy, Treatment

La grossesse et le systeme biliaire

RESUME: La syn these et la secretion des sels biliaires ct du cholesterol ainsi q ue la fonction de la vesicule biliaire sont modifiecs pendant la grossesse. Ces changemcnts son t relies a !'action de l'oestrogene et de la progesterone. La saturat ion de la bile native en cholesterol ct le rapport acide cholique/acide chenodesoxychol ique augmement. La progesterone redu it egalement la contractilite et !'evacuation de la ves icule. Les calculs surviennent chez 2,5 a 11 % des femmes encein tes et som associes a la cho lecystite chez 0,008% a O, l % J'entte e lles. Le traitement operatoire devrait si possible etre retarde apres l'accouchement ou devrait alors s'effecruer de preference au cours du second mmesrre. La papillotomie endoscopique est prohablemcnt la therapie la plus appropriee a la cho ledochol ithiase.

DURING PREGNANCY. BILE FORMA­t ion and ga llbladder function

undergo specific changes which predis­pose to the development of cholelithi­asis. In most patients, ga llstones arc asymptomatic, hut in some they cause

biliary colic, acuce cholecysritis and pancrearit1s. During pregnancy, cholecysrectomy is second only ro ap­pendectomy as a nonobstctric cause of laparotomy ( l ).

Other rarer lesions of the biliary tree

Department of Medicine. St Mrchael's Hosp1ral and U111venicy of Toronto, Toronw, Onwrio Correspondence and reprints: Dr)) Connon, Sr Michael's Hospir.al, 30 Bond Scrcct,

Toronto, Ontario M5B I W8. Tele/Jhone ( 4 J 6) 864-5114 Received for publication November 13, 1989 . Accepted Ma'/ 15. 1990

CAN) GASTROENTEROL VOL 4 No 5 JUI Y/AUC.UST [990

reported during pregnancy include: choledochal cysts, biliary tract carcin­oma and rupture of the cystic duct. In general, these lesions arc not related to pregnancy per sc, and their frequency is similar to that in the nonpregnant population; at best there is a weak as­soci:uion.

This review will examine d isorders of the biliary tree in pregnancy, with emphasis nn the pathogenesis and management of gallstone disease.

NORMAL PHYSIOLOGY Prior to discussion of the patho­

physiology of biliary tract disease in pregnancy, a brief review of the normal physiology is appropnare.

The ch ief constituents of hile a re bile salts, cholesterol, phospholipids, bi lirubin, electrolytes and water. Bile sa lts are conjugated bile acids synthe­sized in the liver from cho lestero l. Their main function is to emulsify dietary fat and thus a id in the digestion and ab­sorption of lipids. Excreted bile acids consist of recirculated bi le acids, the major constituent, and newly syn­thesized hilc acids (2).

The rate of synthc~is of primary hile acids (cholic and chenodeoxycholic acid) from cholesterol in the liver is regulated by the activ ity of 7-a­hydroxylase. The act ivity of this en­zyme is under negative feedback control, dependent on the quantil y of bile salts returning to the liver via the enterohepatic c irculation (3 ).

209

Wrrr ANI) CONNON

The primary hile acids are con­iugated with glycine and taurine, and then sec reted into bile canaliculi. When they ,ire rre ·cm a hove a crinca l concentration , aggregation occurs, lead ing w m1celle formation. Micelles have a h ydrophoh ic cenrre and a hydrophilic ex terior. This prorerty al­lows water-insoluble compounds w be maintained in sn lu1 ion ( 4 ).

Cht1lesterol and lecithin arc water­insoluble compound,. The incorpora­tion of lcc irhin, a phosphol1p1d, into the micelle resulrs in inc reased cholestero l-ca rrying capacity. Th e solubilizat ion of c ho lesterol by these 'mixed' micelles is an important tactor m the prevenuon of gallstone fo rma­tion. Solubility limits of c hole, terol relative co bile sa lt and lec ithin con­centratiom have been wdl defined (5,6). Outside t hese soluhili ty limits bile is supersaturated with c ho lesterol. The term 'lithogenic hilc' refers to its predisposiuon to gallstone formation.

Differences 111 'couplmg rauos' (ie, the amount of cho lesterol carried per molecule of bile sa lt) ex ist between the two primary bile acids. The capacity of chohne to couple with cho lesterol i, gre,ncr than that of chcnodeoxycht)­late. This accounts in pan for the lith ll­lytic properties of c he nodenxycholate compared to the lithogenic properties of cho late (7). In addition to the solu­bility of cho lesterol, other fac tors which play a role in stone formation inc luJe nucleating (8) and anrinuclcming fac­tors (9). These enhance or discourage stone formation, rc:,pect i vcly, but arc of lesser importance compared lo the solubility limits of cho le:,terol. The role n( phospholipid'vesicles in transrnrung hiliary cho lesterol and in the etio logy of gallstones is still being explored .

Bile is stored in the ga llbladder until the gallbladder contract:, and e mptie:, it:, contents into the duodenum. Ahout 90% of bile salts arc actively alwirhed in the distal ileum by d 1ffu:, ion ( 10). The:,e bi le ac ids then return to the liver via the portal c irculation 10 complete the entcrohepa u c ci rculatory cyc le . Bile sa lt~ reach mg the colon ;ire dccon­jugatcd by bacterial 7-a-dehydrnxyla:,e to secondary hile sa lt:, (deoxychol ic a nd lithocholic acid) and ,m· excreted 111

210

the StllOI. Thus 90 tll 95% of the bile salt Iliad b conserved a nd recycled five to

:,even rimes per day ( 11 ). Any mec h anism whereby bi le

cho les terol concentration b increased or hilc acid concentratilm decreased favnurs the formation of c ho lesterol chllle lithiasis, the prmcipal disease of the biliary tract in pregnancy. Patho­genetic facwrs speci fic to pregnancy will bi: discu:,sed in further detai l in the p,1thophy:,iology sect ion .

EPIDEMIOLOGY OF GALLSTONE DISEASE

IN PREGNANCY Th e re is substa ntia l worldwide

variation in the incidence of gallstones. In the United States, pOM mortem studies indicate that about I 5% of the adult population has ga lbtoncs (12). C learly, such studies arc potentia ll y hiascd by the age of the autopsy popula­tion. Eighty-five to 95% o f th ese gallstones arc primarily composed of cho lesternl, whereas in southeast Asia hilirubin stones are more common ( 13 ). Recent Scandinav ian st udies h ave reported a ~ignificant d ecl in e in ga llstone inc idence which has been at­trihutcd to both decreased use of con­traceptives and reduced contraceptive hormonal conten t (14-16).

The Framing h a m s tud y ( 17) reviewed the rate of definite ga llbladder disease (defined by autopsy or surgery) and found an increasing IO yea r in­c idence rate for women as follows: age groups 30 co 39, 40 to 49 and 50 to 62 had respective inc idence rates of 30, 66 and 89 per I 00,000. These figure~ show an inc rease in gallstone dbease with increasing age. In l>Upport of this, age ha~ a lso been shown a positive correla­tion with rate of cholesterol secret ion a nd a negative correlation with hile acid synthe~is, both of which predispme w lithogen,c bile ( 18).

Female:, are 1wicc as likel y to de­velop cholclith iasb as men (17). Thi:, difference hecomes apparent at men ­arc he ;md cont inues th rough the c hild ­bearing yea rs ( 19). It shou ld be noted, however, 1hm with increasing age come, increasing development of ga ll ­~lones in hoth men and women ( l 7,20).

Ohe~ity 1, pos iu vc ly correlated wirh

chnlcli thias1s, pos., ihly hecause Pl the increa~ed rare of cholesterol ,ecreuon in association with ;in unchanged hilr salt secretory ra1e (2 1,22).

Although the influence uf pregnan­cy un ga ll:,tnne 111cidence has hcL·n recognized for many years, the relat1on­sh ip b not quite as c learcut as w,1' formerly thought. The Framingham study ( 17) showed that part! y mcreasc,I t he risk of ga llstone formatilm after four or more pregna nc 1es. More recc111 studies have cunf"i rmed the associauon with pregnancy hur suggest th ,n the in. creased risk is confined w younger rrcg­nant women. Scragg ( 2 3) found that ,1'

the age offirst pregnancy incrca~ed, d1,· risk of gallsrnne fell. Simi larly, the Ill· crea~ed inc ide nce of gal bi ones tn con· trnceptive users is confined to women less than 29 years of age. T hese finding, imply rhm pregnancy and fema lc :,ex hormones unmask a subpnpulatinn of you nger wom...:n who are particularl1 susceptible to cholclithiasi~.

In summary, the major risk fr1ctnr, for cholesterol gallswnes me femall' gender, pregnancy, nbesi1y, age and r,1-c ial origin.

PATHOGENESIS OF GALLSTONE FORMATION

IN PREGNANCY Changes in both bi le chemistry and

gallb ladder motility have been offered as an explanation for the epidcm1nlng1-cal association of pregn,rncy and or,11 contraceptives with increased gallsronc formation.

C ho lesterol sa turation ti bile and rate of ~ecretion of cholesterol arc tn·

creased by both pregnancy a nd female sex stero ids (24,25). In ,1ddiuon, preg­na ncy and ,ex steroids lead to an in­uca sed m t iu of c h ol ic aci d 10

chenodeoxycho lic acid in hilc. T he ntl

rewlt b incrcascd bile li t h\1genicity. Kern (26) found that admintstrauon

of oral contraceptive medications led lo in c reased secre ti on of htl,ary choleste rol, wh ich directly parallcleJ cholesterol ~yn thesis and hepat IL up­take of c hylomicron remnants. In a companion puhlicatllll1 (27), rhe sanw workers repmtcd a direct rclat ionsh1p hetwcen both hilc acid and c ho lesterol synthesis 111 response to Clmt raccpll \'e

C AN J G ,\STROcNHRUI Vm 4 Nu 5 Ju, Y/ A tJUUS r 1990

srerrnds. In tht~ setting, e~tmgen and

progesrcrlme c1uscd a preferential in­cre ase in c h n l ic acid relative to

chenodeoxycho lic acid, thus cnhanc­

lllg the lithogcnic tendency of hile. It was sugges t e d that estrogen a nd progesterone have differe nt effects, estrogen act ing mainly tn increase hepatic uptake o( cholesterol possibly by increns ing receptor acti vi ty, and progesterone ca u si ng in c reased

hcpatocyte secret ion nf cholesterol by inhibiting the activity llf t he cholesternl-c~t er ifying e n c:y me acyl­coenzyme A: cholestero l acylcrnns­ferasc. The effect llf. est rngen on hepatic

cholesterol upt a ke is supported hy ano ther s tud y in pn~tmen o p;1usa l

women in whom estrogen aJmmistrn­

tion in c reased biliary chnlc~tcrol

without affect ing intestinal ahsorpt ion or hepat ic synthesis (28).

The role nf phnsphnlipid vcsicks or nucleating a nd antinucleating factors in stone format ion has not hecn ex­

plored during pregna ncy or in response to sex hormones.

A recent prospective study frum Italy (2.9) has demonstrated the Jyrn1-111ic nature of gallstone format ion and <lissnlution during pregnancy. The for­mation of horh sludge and stones in­

creased progress ive ly during pregna ncy with a cumulative inc idence of sludge and stones immediate! y after Jc! 1 vt:ry of 41 and 9.6%, rt:spectively. In many ,1f these women, sludge and stone~ disap­

peared hnth during and fnllnwing preg­

nancy. The effects uf t:strogt:n on biliary

cholesterol saturation arc suppo rted l:,y a recent study on cst r()gcn - induccd

ga llstnnc formati lm in males. The patients were hcmg t rt:;i l cd for car­cinoma of the prostate with est rogen,

which resulted 111 tivt: of 37 patients on estrogen developing gallstones, while

none n( rh e co nt ml nrchidccromy patients tkvel-1ped stont:s. Biliary lipids and phosphnlipids a b o inc rea~t:d and chenoJcoxyc holi c acid dcc re;:i scd moderatel y in d1 l' cst roge n -tn.:aied

group (10). Pregnancy also has a deleterious ef­

fect on gallhladdcr contract ility which hcgins during the second trimestt:r ( 31) and results in inc reases in ga llhladder

volume during fasting - as well as in residua l volume a fter cnntrac1 io n -which ,\re l wicc those of nl1npregnant

females ( 3 l, 32). There b a lso a decreased rnte O 1) and percentage ( H, 33) of emptying. The common bile Juel size remains within normal limits (34).

Progesterone is believed responsible for these effects hy inhihition of smooth muscle fu nc ti on. Experiments us ing

pregnant guinea pigs show decreased gallhladdcr conrractility in response to

acctylcho linc and cholecystnkinin , hu1 no c han ge in the face of inc reased extracellular potassium. Thb result sug­

gt:sts that rrogesterone may spt:c ifica lly affect a step in tht: cxcital inn-contrac­

tion coupling process common tu hoth acerylch,1line and cho lecystokinin (15).

It is bcl ievcd thm the comhina t inn of ga llbladdl'r stas is and lithngenic hi le al lo ws (,1rmat ion of cho lesterol crystals and eventua l gallsr,me,.

CLINICAL ASPECTS OF CHOLELITHIASIS IN PREGNANCY

The maJor areas 10 be discussed re­latt: to differences tn 1nudencc, clinical features, diagnns is and management lif

sy111ptrnna1 ic ga llswncs m pregnancy. Incidence: A 1 th,,ugh the rt: is good

evidence for the de novn format inn ,,r gallstones and sludgt: during pregnancy, it is nnt dear fn im the ava ilable litera­

l urc wht:t her I ht:rl' 1s ,1 bo an i ncreasc 111

tl1t: incidence of symptomatic galbwne d ist:asL'. A t any rntc, htliary 1rac1

problems arc relativd y uncommon in pregnant women, falling well behind appendicll is ;1, a causl' of nonohstt:tric

hipamtomy. The inciden ce of ga ll ­stones in prt:gnancy has been quoted as ranging frnm 2.5 tll 11.3% (37- 39), hu t any consideration of these figure.\ must

take into account tht: lt:ndency towards mcreascd srnne format1,1n throughout prcgrnmcy, as well as the dyna111 1t na­tu re uf stone formallon ,1 nJ dissnlut llm. The prevalence of acute cho lecystit b in

pregnancy ranges fro m 0.008 w 0.1 % ( 1.40). C linical features: Tht: manifestations of bi lia ry colic arc similar tn pregnant and nonpregnanr wo men . Pain, whic h

lasts up to SL'Vc ral hours, 1s s ituated ll1

1hc epigastriurn ur ri g ht hypo-

CAN] G1\STROl:NTl:ll.1.)L V1)L 4 N1.) 5 JULY/AUUlbT 1990

Pregnancy and the biliary system

chonJrium ( 4 l -4 ~).There isno spccil1c

relationship to ingest ion of fatty foods, and in the nonprt:gn,m1 pa11ent, htl1ary C(1[i( b m,,rl' commo n during the nigh t

versus day time. U nlike peptic ulcer pain, its occurrence is unprcdicrnhk-,

and episod ic upper ahdnm111al pain nc­curring daily 1s unlikely to he due tn

biliary colic. Acute cholccyst it is may occur ,ll an y

t ime during pregnancy. It cau~cs more

severe pain of longer durnt inn than bi liary colic nnd is assoc i;1tl'd with

tendemess and guard ing in t ht: nght hypochondrium. Varying degrees nf feve r, vo miting , tach ycard ia and

hypotensinn occur, depending on I lw severi ty of ga ll bladder sepsis.

The course of acute c ho lecyst it 1~

may he complicated by jaundice dul'

either tn the spread o f inn,1 mmatory edema to thl' common bi le duc t , or 10

c hnlcdoc ho l ith iasis ( 44 ). The Inner prohkm may al,o give ri se to p:rncrcmitis or c h o langit is (45,46). Acute c hnlccyst itis must he dis tin­guished fmm appendicitis, pancreat i1 is,

pe rforated pcpu c ulcer, pncumo ni,1, acute fatty li ver of pregna ncy and prc­ec lampsi,1, a ll of whic h c;1n caw,c

~imila r findings.

INVESTIGATIONS Biochemistry: Uncomplicated bil ia ry c,i li c causes nn ch.1ngc, in live r (unc­ti on t ests or white cell cou nt. Acut e

c holccys titis may he accompanied by a va rying degree o f lcukocywsis a nd cha n ges 111 l ivt:r funcuon c au st:d ell h t: r hy ndj,1ccnl hep,lli c innamma­tinn, cnmmon duc t edema nr c holedn­c holith1a,1,. Accordingly, depending

on the rclati vl' contrihutio ns of these ch anges, either tlw aminorransfcrnscs m a lkaline pho~pharnse may he in ­c reased . Acute c ho lecyst it b may als,1

he aCCllmpanied hy an up rn twofold e levat ions of sc rum a m ylase (44 ) . U rcater rises in a m ylase rai se I hl' pos­sihili1y of eitht:r acute panc re,1titis or choledochol ithiasb.

Pregnancy is no rmally associated with raised levels of a lka l inc phrn,pha­

tase of placental origin which may he H

source o( confusion. Measurement of

g;:unma-glu tamyl transferase can hl' lp confirm the hepatic migin of alkaline

211

WITI AND CONNON

phosphatase. Other hepauc complica­tions of pregnancy such as acute fatty liver or pre-eclampsia will also affect liver function tests. Ultrasound: The advent of ultrasonic scanning has provided a safe, simple, rapid and accurate method of evaluat­ing patients with poss1tile gallbladder disease, making the need for oral and intravenous cholangiography virtually obsolete. Ultrasound has become in­creasingly accurate with time, and 95 to 99l){1 accuracy in dugnosing choldithi­asis has been reported (47). The ultra­sonic diagnosb of acute cholccyscitis has a semmviry of 94%, a specificity of 85% and an overall accuracy of 88% ( 48). Aside from visualization of gall­stones themselves, pericholecystic OuiJ, distension and thickening of the gallbladder wall, and ultrasound trans­ducer-induced pam over the gallblad­der arc suggestive of cholecystitb ( 49). The demonstration of dilated bile ducts on ultrasound examination is most likely due to choleJocholithias1s and should be confi rme<l by endoscopic retrograde cholang1opancreatography, which can tie followe<l hy en<lo~copic papillocomy.

NonvbL1alization of the gallhla<l<ler on ra<l101sotope scanning may confirm the presence of cholecysritts, but be­cause of radiation risk to the fetus, albeit small, scanning shoul<l only be per­formed if the diagnosis remains unclear an<l the patient ,~ deteriorating.

MANAGEMENT AND TREATMENT

Asymptomatic stones in the gallbla<ldcrof a nonpregnant individual shou ld be left alone (I). Pregnant patients who develop acute cholecys­t it is shoul<l receive conservative management 1111tially, consisting of nasogastric suction, intravenous Oui<ls, analgesics and anubiorn.s ( 1f sepsis is suspected) ( l,42,43,50). Resolution rates of 77 (51) to 84% (52) can tie expected with medical treatment.

The timing of elective cholecystec­tomy following an ep1:,ode of acute cholccystitis m pregnancy 1s controver­sial. Some surgeons advocate cholecys­tectomy during the secon<l trimester, whereas others feel that the likelihood of a seconJ attack b sufficiently small,

212

and Its outcome sufficiently benign to warrant po:,rponing elective operation unul after Jel1very. The greatest ha:ard of waning relates to unsuspected cht)lc­dochol ith iasis, but the 1ncrea:,ing availability of endoscopic papillocomy diminishes this risk. ln area where ready access to skilled en<loscopy is limite<l, one may argue for a more ag­gressive approach to cholecystectomy dunng pregnancy, especially <luring the secon<l trimester, if liver function rests arc abnormal or bile ducts dilated.

If surgical intervention is unavoid­able, then the second trimester is con­si<lcre<l an optimal period, since the highest risk period for spontaneous abomon has passed and the uterus has not yet obscure<l the surgical ficl<l ( 1.4 3,52,53 ).

Maternal morbidity and monaliry Jo nor differ from that of the nonpreg­nant populauon (39,41). Fetal mor­tality is approximately 5% (39,53) but can he as high as 15% if surgery takes place in the first trimester ( 54,55 ).

In the case of patients with choledocholirhiasis during pregnancy, endoscopic papillotomy will likely be­come the treatment of choice (56). Complications of this procedure in­clu<le blec<ling, pancreatitis, cholan­gitis and duodenal perforation. The complication rate in skilled hands is less than 5%, an<l appropriate shielding can d1min1sh radiation exposure of the fetus. In view of the young age of these patients and the possibility of further gallbladder - as opposed to bile duct -comp lications, elective cholecystec­romy should he done after delivery.

Gallstone pancreatitb has been as­sociate<l with a high fetal mortality of 60% (57), but a more recent study <lid not support these figures an<l proposed that the poor fetal outcome previously reponc<l was a direct result of laparo­tomy done early in pregnancy (46).

OTHER LESIONS There are a number of reports of

choledochal cysts becoming syrnp­tomauc during pregnancy (58,59). Such cysts usually present at an early age and are more common in females (4: I ratio) and Orientals. Of the four types of cysts, type I 1s encoun tercd

most frequently. This type 1s defined a, spherical <lilaunon of the commlln h1lc duct with dbtal narrowmg (58). Typi­cal features include pain, jaundice ant! right upper quadrant mass.

It has been ,ugge~t ed thac the com pres:,ive effect of the enlarging uterus impairs emptying of the choledochal cyst, leading to the development or won,ening of symptoms relate<l co tht: cyst (59). The comcidencal finding ot a

cholangiocarcinoma complicating a chole<lochal cyst in pregnancy ha:, been reporte<l (60).

T reatmcnt of asymptomatic cyst­can be deferred uncil after delivery, at which rime the appropriate treatmen1 consists of resection to avoid develot ment of cholangiocarcinoma. The onset of compl1canons such as obstruc­tive jaundice or cholang1rn during pregnancy shou ld he treated by per­cutaneous transhepatlL dramage. Two cases of rupture (61 ,62) and one of 'im­pending rupture' (63) of choledochal cysts have been described in prcgnanq nnd arc clear indications for surgery.

Spontaneous rupture of the common bile <lucr in pregnancy has nbo been described (64 ). The flssociation with pregnancy 1s likely comcidental.

ACKNOWLEDGEMENTS: The ,1urhur, chank Mrs G Cole for her typing a,si-tann· m the preparation of thb manmcript.

REFERENCES I. Woodhouse DR, 11:iykn B. Gall­

bladder disease compl1carin)! pregnan­cy. Aw,r N Z Oh,cc1 Ciynecnl 1985;25:233.

2. Sherlock S. Disease:, of th<! Liver anJ B1li.u1 System, 8th edn. Oxford, Bl.Kl well Sc1enuf1c Puhl1c11mn,, 1985:25.

3. Mmh,Kh El l. I lcpatit synthesis of hik· acids. Arch Intern Ml'd 1972;130:478 87.

4. Sherlock S. D1sea,e, of the Liver ,mJ Biliary System, 8th edn. Oxford:Bl,tLk­wcll SL1cnuf1c Puhlic,H1t111s, 1989:656.

5. Adm1ranJ WI I, Small DM. The phys1cochcm1cal h<1sis of cholesterol galbtone fllrmat1on 111 man. J Cl111 Invest 1968;47:1043-52.

6. Carey MC, Sm,111 DM. The phy,Kal chem1,try nf Lhole,terol soluhiluy 111

hile. J Clin Invest 1978;6 I :998-1026. 7. Smallwood RA, Hoffman NE. Bile arnl

struuure ,1ml hiliary secreuon of

CAN J GA~"TROINTF:Rt)L VOi 4 Nu 5 JUL Y/AUlil l'-."T 1990

r

cholesten,I and phospholipiJ m the cat. Gastrocntcmlogy 1976; 71: I 063-6.

8. Bumstem MJ, llson RG. Petmnica CN, Strasberg S. EviJcnu: for a potent nucleatmg factor m the gallbladder bile tif patients with chole,terol gallsrnnes. Gasrmentemlngy 1983;85:801-7.

9. Kibe A, Hol:bach RT, LaRusso NF, et al. Inhibition n( chole,tcrol crystal fonrnmon hy apolipoproreirn. 111 super­saturated model bile. Science 1984;22 5: 514-6.

10. Lack L, Weiner IM. The role of rhe in­te,rine during rhe enreroheparic c1rc ulation of hde salts. G,1stmencerology 1967;52:282-7.

II. Small DM. Dowling RH, Redmger RN. The emerohepauc c1rculauon of bile salts. Arch lmem Med 1972; 130:552-73.

12. Glenn F. Biliary rmct d1,ease. Surg Gynecol Obsret 1981;153:401.

13. Small DM. The fnrmamm and treat­ment of gallstone,. In: Schiff L, Schiff ER, eds. Disease of rhe Liver, 5th edn. PhilaJclphta: L1ppinctltt, 1982: 151-66.

14. Evmn S, Frnnkcl M, Diamant Y. Biliary disease m young women and its association with pregnancy or oral con­traceptives. Inc Surg 1982;67:448-50.

15. Jamfclt-Samside A, Eriks,on B, Leissner KH, Samside G. Ga llblaJder disease related to use of ora l contracep­tives ~nd nausea in pregnancy. South Med) 1985;78:1040-3.

16. Janzon L, Aspclm P, Eriksson S, Hilde II J, Trill E, Ostberg H. Ultrasonograph1c screen mg for gallstone disease 111 m1ddle-agcd women. Scand J Gascrocnterol 1985;20:706-10.

17. Friedman GD, Kannel WB, Dawber TR. The epidemiology of gallbladder disease: Observations m the Framingham study. J Chron Dis 1966;19:273-92.

18. Einarsson K, Nilscll K, LeiJ DB, Angclin B. Influence of age nn secre­tion of cholesterol and synthesis nf bile acids by the liver. N Engl J Med 1985;3 I 3:2 77-82.

19. Nilsson S. Gallbladder disease and sex h.ormoncs. A statistical study. Acta Chir Scant! 1966; 132:275-9.

ZO. Zahor Z, Sremb NH, Kaga NA, Cl al. Frequency of cholclirhh1si:, in Prague and Malmo. An auwpsy study. Scand J Gamoenterol 1974;9:3-7.

ZI. Morrissey K, Panveliwalla D, McSherry C, Dietrick J, N icmann W, Gupta G. Effects of contraceptive steroids and pregnancy on bile com­position and kinetics in rhe baboon. J Surg Res 1977;22:598-604.

22. Honore LH. Cholesterol cholelithi.1sis in adolescent females. Arch Surg I 980;115:62-4.

2 t Scragg RKR, McM1chael AJ, Seamark RF. Oral contraceptives, pregnancy and endogenous estrogen in gallstone disease. A case-control study. Br Med J 1984;288: l 795-9.

24. Kcrn F Jr, Evcrson GT, DeMark B, et ,ii. B1lmry lipids, bile acids and gallbladder function in the human female - Effects of pregnancy and the ovulatory cycle. J Clin Invest 1981 ;68: 1229-42.

25. Hcnnion LJ, Mott DM, Howard BY. Oral cnmraccpt1ves raise rhc cholesterol sarurar1on of bile by increasmg hi! iary ch,)lesrcrol secretion. Metabolism 1980;29:J 8-22.

26. Kem F Jr, Everson GT. C,lmmceptive steroids mcreasc chnlcsrcrol bile: Mcchanbms ol acci,ln. J Lipid Res I 987;28:828-39.

27. Everson GT. Fennessey P. Kern F Jr. Contraceptive stl·n11ds alter I he steady­stare ktnettcs of bile acids. J Lipid Res I 988;29:68-76.

28. Everson OT, Kern F Jr. Mechanisms of gallstone formation 111 poscmenopausal wnmcn caking c.:nnjugared t'1>tmgen (Premarin). Gasrroenrerology 1988;94:A 5 38.

29. Mminghini A, Ciamhrn M, Baccclliere P, Raim,lmit) M, Pagliaro L. Sludge, stones and pregnancy. Gasrrocmerok1gy 1988;95: 1160-l.

30. I lenriksson P, Einarsson K, Eriksson A, Cl al. Estrogen induced gallstone forma­tion 111 males. J Clin Invest l 989;84:811-6.

31. Brnvcrman DZ, Johnson ML, Kern F Jr. Effects of pregnancy and contracep­tive stcmtds nn gall bladder functton. N Engl J Med 1980; 302:362-4.

32. K1rkinen P, Ylosrnlo P, Heikkinen J, Maenrausrn 0. G,1llbladder function and maternal bile acids in inrra­hcpatic cholesrasis of pregnancy. Eur J Ohstet Gynecnl Reprod Biol 1984; 18:29-34.

~ 3. Ylnscaln P, Kirkinen P, Heikkinen J, Maenrnusa 0, Jarvinen PA. Gallhlad­der volume and scrum bile ,icids in cholestasts of pregm1ncy. Br J Obstel Gynaccol l 982;89:59-61.

34. Mintz MC, Grumbach K, Arger PH, Coleman BG. Sonographic evaluan,m of bile duct size during pregnancy. AmJ RaJiol 1985;1.45:575-8.

35. Ryan JP. Effect of pregnancy on gallbladder conrracriliry in the guinea ptg. Gastroentcrology l 984;87:674-8.

36. Leissner KH, Wedel H, Schersten T. Comparison between the use of oral contraceptives and che incidence uf surgically confirmed gallstones disease. Scand J Gamoenterol 1977; 12:893-6.

37. Careen KJ, Pulliam RP. Cholelithh1sis m pregnancy. West Virgini,1 Med J 1985;8 I: 75-6.

38. Willwm,on SL, Williamson MR.

CAN J GASTROENTEROI VOL 4 NO 5 JULY/AUGUST 1990

Pregnancy and the biliary system

Cholecy,wsonography m rrrgnancy. J Ultrasound Med I 984;3:329- 31.

W. Stauffer RA, Adam., A, Wygal J, Lavery JP. Gallhladder disease 111 preg­nancy. Am J Obstel Gynecnl 1982; 144:661-4.

40. Friley MD, Douglas G. Acute cholecys­titis in pregnancy ;md the pucruerium. Am Surg 1972;18:3 14-7.

4l. Hill LM,Johnson CE, Lee RA. Cholecysrecromy in prcgnan<.:y. ObstetGynecol 1975;46:291-3.

42. De Yore GR. Acllte abdominal pain in the pregnant patient due m pancreatitis, acute appendicitts, cho lecystitis or peptic ulcer disease. Clin Perin.no! 1980;7: 349-69.

4 3. Simon JA. Biliary tract disease and rc­lared surgical disorders dunng pregnan­cy. Clin Obstet Gynccol l 983;26:810-2 l.

44. Block P, Kelly TR. Management of galbmne pancreariris durmg pregnancy and the postp,1num period. Surg Gynecol Obstet 1989; l 68:426-8.

45. Hacmrnerli UP. Jaundice during preg­nancy with special reference to recur­rent jaundice during pregnancy and its differential diagnosis. Acta Med Scand l 966;444(Suppl): I.

46. McKay AJ, O'Neill J, lmne CW. Pancrcatifr,, pregnancy and gallstones. Br J OhMet Gynaccnl 1980;87:47.

47. Lamg FC. Diagm»tic cv .. 1luar1on of patients with ,u,pected acutc cholecys­rnis. Radtol Clm North Am 1981;21:477.

48. L11ng FC, Fcderlc MD, Bmokc Jcffcry R, Brown TW. Ultrasonic cvaluari,n1 of patients wtth :icute righr upper quadrant pain. Radiology 1981 ;140:449-55.

49. Zeman RK, Jaffe Ml I, Gmnr EG, el al. Imaging of the liver, hiliary tract and pancrca:,. Med C lin North Am 1984;68: 1535-6 3.

50. I lolman KG, Montgomery PJ, Dcvahhaktunt D. Gallbladder &,ease 111 pregnancy. Am Fam Phys 1985;32:l47.

51. I liat JR, Hiat JCG, Williams RA, Klem S. Ri liary d1se,bc in pregnancy: Strategy for surgical management. AmJ Surµ 1986;151:263-5.

52. Lander:, D, Carmona R, Cmmbleholme W, Lim R. Acute cholecy:,tit1s m pregnancy. Obstel Gynccol 1987 ;69: I 3 1-l

5 3. Kammerer WS. Non-obstetric ,urgery during pregnancy. Med Clin N,1rth Am 1979;6:1157-64.

54. Macbeth RA. Acute surg1c~l disease of thc abdomen complicating pregnancy. CanJ Surg 1961;4:4 19-29.

55. Grecne J, R,1gers A, Rubin L. Femi Ins, after cholecysrecmmy dunng pregnancy. C.rn Med As,oc J 196 3;88:576-7.

Z l 3

56. Baill ie J, Cums SR, Cotton PB. EndoscopiL m;magcmcnt of d,0I.:­d1xholith1as" durmg pregnancy. Ga,tmcntcmlllgy 1988;94:18. (Abs!)

57. Prinrcn KJ, On RA Chnlccy,rccwnw during prcgn.mq Am ~urg 1978;44:4 H-4.

58. Tnylor TV, Brigg JK, Rus,cll JGB. Torr,111<:c B. ( 'holt•dnchal qst ol pregnancy. J R Coll Surg him 1977-8;22- l:424 7.

214

59. Angel JL, Knuppd RA, Trahin J. Cholcdllchnl ..:y,r cnmplic,Hmg ,11win

gc,wu1m. Slluth Medi 1985;78:46 3-6. 60 11evoc LO, Mossa AR, Levin B. !'reg

n,11Ky cllmplit att'd hy t•xrrahepauc biliary tract carc inrnna. A Ghe report. J Rcpmd Med 1983;28:153-5.

61. Saunder~ P, Jackson HT. Rupture of choledochu; cyst in prt•gnanq. Br Med J 1969; 3:573-4.

62. Friend WO. Rupture uf cholcdochal

l y,t during nmf,m:mcnt. Br I Surg I 9'i8;46, I 5 5-7

6 3 K1tah,un,1 A, I la, knc,, ~), Moy111h.1n PO, Wt·hh WR 1\ l.irg.: d,oleth h.il q·,t ,, 1rh impend mg ruprurc Br I ',ur1•

ll.Jtl4;71 .156. 64. I t'may M, Urnnger I , Ver-t:hcklc·n ( i,

l~1a:rd Y. [)11g11,1v I , L.wrnc P ~pnn· cancous rupture ,,I rhe nm111111n h,k duct during prcgn,mcy. ( ·,111 Med A,,11cJ 1980;122·14-5.

(' ·\:,.; J ( ~. \qRl 11:NTERl 11. Vl)I 4 Nt 1 5 Ju Y/ Al "tJUST 1990

Submit your manuscripts athttp://www.hindawi.com

Stem CellsInternational

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Disease Markers

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014

Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Parkinson’s Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com