Intestinal bile acid malabsorption in cystic fibrosis

Transcription

1 Gutl993;34: ntestinl bile cid mlbsorption in cystic fibrosis Gstroenterology nd Liver nit, S O'Brien H Mulchy H Fenlon A Burke J Hegrty Adult Cystic Fibrosis Centre, M X FitzGerld duction nd Reserch Centre, A O'Broin nd Deprtment of Nucler Medicine, St Vincent's Hospitl, lm Prk, Dublin, relnd M Csey Correspondence to: Dr J Hegrty, Liver nit, St Vincent's Hospitl, lm Prk, Dublin 4, relnd Accepted for publiction 15 December 1992 S O'Brien, H Mulchy, H Fenlon, A O'Broin, M Csey, A Burke, M X FitzGerld, J Hegrty Abstrct This study imed t exmining the mechnisms prticipting in excessive fecl bile cid loss in cystic fibrosis The study ws designed to define the reltion between fecl ft nd fecl bile cid loss in ptients with nd without cystic fibrosis relted liver disese; to ssess terminl ilel bile cid bsorption by seven dy whole body retention of selenium lbelled homoturocholic cid (SeHCAT); nd to determine if smll intestinl bcteril overgrowth contributes to fecl bile cid loss The study popultion comprised 4 ptients (27 men; medin ge 18 yers) with cystic fibrosis (n=8) nd without (n=32) liver disese nd eight control subjects Fecl bile cid excretion ws significntly higher in cystic fibrosis ptients without liver disese compred with control subjects (men (SM) 21-5 (24) nd 73 (12) umol/kg/24 hours respectively; p<1) nd ptients with liver disese (79 (13) umol/kg/24 hours; p<1) No correltion ws found between fecl ft (g ft/ 24 hours) nd fecl bile cid (umol/24 hours) excretion ight (33%) of cystic fibrosis ptients hd seven dy SeHCAT retention <1% (norml retention >2%) SeHCAT retention in cystic fibrosis ptients with liver disese ws comprble with control subjects (3 (SM) 8-3% v 36-8 (59)%; p=ns) while SeHCAT retention in cystic fibrosis ptients who did not hve liver disese ws significntly reduced (19-9 (38); p<5) Although evidence of smll bowel bcteril overgrowth ws present in 4% of ptients no reltion ws found between breth hydrogen excretion, fecl ft, nd fecl bile cid loss The results re consistent with the presence of n bnormlity in terminl ilel function in ptients with cystic fibrosis who do not hve liver disese nd tht defect in the ilel bsorption of bile cids my be contributory fctor to excessive fecl bile cid loss Fecl bile cid loss in cystic fibrosis is unrelted to the presence of intrluminl ft or intestinl bcteril overgrowth (Gut 1993; 34: ) xcessive fecl bile cid loss is well recognised in ptients with cystic fibrosis'" nd hs been ttributed to n inhibitory effect of intrluminl unhydrolysed triglycerides on the intestinl bsorption of bile cids Some studies, however, hve shown no correltion between fecl ft excretion nd fecl bile cid loss suggesting tht dditionl fctors re responsible for bile cid mlbsorption in cystic fibrosis3 Thus in vitro studies hve shown defect in the terminl ilel bile cid ctive trnsport mechnisms in ptients with cystic fibrosis, which if present in vivo, would lso contribute to excessive fecl bile cid loss9 ' n ddition, intestinl bcteril overgrowth, resulting from prolonged intestinl trnsit nd stsis," my result in deconjugtion nd dehydroxyltion of bile slts nd contribute to impired bile cid bsorption nd fecl bile cid loss xcessive fecl bile cid losses hve not been found in ll studies in dult ptients with cystic fibrosis32 This finding hs been ttributed to the incresed prevlence of heptic dysfunction, with ssocited impirment of bile cid synthesis nd contrction of the totl bile cid pool, in dults with cystic fibrosis3 The objectives of this study in n dult popultion of ptients with cystic fibrosis were to: (1) define the reltion between fecl ft nd fecl bile cid excretion in ptients with nd without liver disese; (2) to discover if defect in the ilel bile cid ctive trnsport mechnism contributes to fecl bile cid loss; nd (3) to ssess the contribution of smll bowel bcteril overgrowth to fecl ft nd fecl bile cid losses Methods PATNTS The study popultion comprised of 4 ptients with cystic fibrosis dmitted to the Adult Cystic Fibrosis Centre for evlution of their respirtory or heptic stte, or both Most ptients were receiving stndrd tretment with bronchodiltors, ntibiotic prophylxis ginst pseudomons or stphylococcl infections, or both, nd pncretic enzyme supplements The presence of heptic disese ws determined by bnorml liver biochemistry tests (gmmglutmyl trnsferse >5 /1, 5'nucleotidse >15 /1) of t lest six months durtion, histologicl evidence of fibrosis/cirrhosis on liver biopsy nd the presence of portl hypertension, or both ight ptients in whom there ws no evidence of gstrointestinl, pncretic, or heptobiliry disese served s control popultion Dietry dvice to chieve totl energy intke of 12-15% of the recommended dily llownce for ge,'3 with pproximtely 4% of the totl energy intke derived from ft, ws given to ech ptient All ptients received ft nd wter soluble vitmin supplements nd none were tking turine supplementtion FACAL FAT AND BL ACD ANALYSS Fecl ft nd fecl bile cid nlysis ws performed on 17 ptients with cystic fibrosis (five with liver disese) nd eight control subjects Fecl smples were collected over three dys during which t lest 5 grms of ft were ingested per dy The dietry intke over the 72 hour collection period ws noted nd ft intke Gut: first published s 11136/gut on 1 August 1993 Downloded from on 7 June 218 by guest Protected by copyright

2 1138 O'Brien, Mulchy, O'Broin, Csey, Burke, FitzGerld, Hegrty TABL Cliniclfetures ofcysticfibrosis ptients with nd without liver disese No liver Liver disese disese p (n=32) (n=8) Vlue Medin ge in yers (rnge) 2 (13-32) 15 (14-21) NS Men:women 22:1 5:3 NS Pncretic supplements 3/32 6/8* NS Meconium ileus equivlent 17/32 5/8 NS Body weight (%BW (SM)) 84-2(2-8) 84 5(2 8) NS BW=del body weight; NS=not significnt; *=one ptient pncres sufficient clculted in grms/dy Three dy stool collection were stored t - 2 C nd were subsequently nlysed for ft nd bile cid content FACAL FAT MASRMNT Fecl ft nlysis ws performed using the method of vn de Kmer'4 nd expressed s g ft/ g stool/24 hours The coefficient of ft bsorption (CFA) ws clculted from the dily dietry ft intke nd the dily stool ft output nd expressed s percentge of the dily ft intke CFA Dily ft intke (g)-dily stool output (g) Dily ft intke (g) FACAL BL ACD MASRMNT Bile cids were extrcted from 1 mg liquot of dried homogente of feces Fifty microlitres of [14C]-sodium cholte ws dded s n internl stndrd to llow ssessment of recovery rtes t the end of the extrction procedure Bile cids were hydrolysed under lkline conditions t 22 C nd were subsequently neutrlised with hydrochloric cid nd extrcted with diethylether Totl fecl bile cids were mesured using 3-hydroxysteroid dehydrogense ssy'5 nd expressed s tmol bile cid/g stool/24 hours The results were lso expressed s mg glycocholte equivlent bile cid/g stool/24 hours by dding glycocholte stndrd to the stool specimen before nlysis SLNM HOMOTAROCHOLC ACD (sehcat) RTNTON The seven dy retention of 75selenium lbelled homoturocholic cid (SeHCAT), bile cid specificlly bsorbed by n ilel ctive trnsport mechnism, 17 ws mesured in 21 cystic fibrosis ptients (six with cystic fibrosis relted liver disese) nd eight control subjects One TABL Feclft ndfecl bile cid excretion in cysticfibrosis ptients with nd without liver disese No liver disese Liver disese Control (n= 12) (n=5) (n=8) FF (g ft/g stool/24 hours)x (8-6) 5 (15-1) 26-9 (3 5) CFA(%) 85-7(3 9) 81-3(9-1) 97-1( 5)* FBA ([smol/kg body wt/24 hours) 21-5 (2 4)t 7-9 (1-3) 7-3 (1-2) FBA (mg bile cid/g stool/24 hours)x (32-5)t 86-5 (28-6) 1-3 (12) Seven dy SeHCAT retention (%) 19-9 (3-8) 3- (8 3) 36-8 (5-9) *=p<-1 compred with cystic fibrosis ptients; t= p<- compred with liver disese nd controls; t p<5 compred with liver disese nd controls; =p<5 compred with controls FF=fecl ft, CFA=coefficient of ft bsorption, FBA =fecl bile cids TABL Hydrogen breth tests in cystic fibrosis ptients with nd without liver disese No liver Liver disese disese p (n=28) (n=5) Vlue Fsting breth H2 (ppm) > 12< NS >75 8 NS Fsting H2< 12 ppm x 1% post sucrose 3 1 NS H2 breth test Positive 16/28 4/5 NS Negtive 12/28 1/5 NS H2=hydrogen; ppm=prts per million; NS not significnt microcurie (37 kbq) of SeHCAT ws given orlly in cpsule form to ech subject Whole body retention (% of dose) of selenium rdioctivity ws mesured on two occsions using shllow shield whole body counter (Cmberr Accuscn) three hours nd seven dys fter ingestion of the rdiolbelled isotope HYDROGN BRATH TST ANALYSS ncresed breth hydrogen excretion fter the ingestion of glucose nd incresed breth hydrogen excretion in the fsting stte, is useful indictor of intestinl bcteril overgrowth 89 Hydrogen breth tests were performed on 33 ptients with cystic fibrosis including five ptients with cystic fibrosis relted liver disese nd eight control subjects None of the ptients hd ingested lctulose in the preceding 36 hours Breth hydrogen concentrtion ws mesured using n exhled hydrogen monitor (Keymed) After n overnight fst (minimum 1 hours) two 2 ml liquots of end expirtory breth smples were obtined using modified Hldne-Priestly tube Breth hydrogen ws mesured immeditely nd if less thn 12 prts per million (ppm) 5 g of sucrose ws given orlly After ingestion of sucrose, breth hydrogen ws mesured t 2 minute intervls for 16 minutes f during this period breth hydrogen incresed by 1% or more the test ws considered bnorml f the fsting breth hydrogen ws greter thn 12 ppm fsting ws continued for up to 14 hours nd breth hydrogen persistently greter thn 12 ppm t the end of this period ws considered bnorml FFCT OF ANTMCROBAL TRATMNT To find out if smll bowel bcteril overgrowth contributes to fecl ft nd fecl bile cid losses four ptients with positive hydrogen breth tests nd excessive fecl ft nd fecl bile cid losses were treted with seven dy course of orl metronidzole (4 mg three times dily) Hydrogen breth tests nd three dy stool collections for fecl ft were repeted t the end of the course of tretment STATSTCS All dt re expressed s men (SM) Differences between groups were compred using Wilcoxon rnk sum test Fecl ft nd fecl bile cid vlues before nd fter metronidzole Gut: first published s 11136/gut on 1 August 1993 Downloded from on 7 June 218 by guest Protected by copyright

3 ntestinl bile cid mlbsorption in cysticfibrosis ~1*!-- n co Q ) C) - * +- * Cystic fibrosis no liver disese + Cystic fibrosis liver disese + * r = -1 p = -7 + r= -7 p = 2 Figure 1: Correltion between feclft ndfecl bile cid excretion in cysticfibrosis ptients with nd without liver disese 'C LL co Cu Q) z 8 r- Rnge of norml controls No liver disese _~ Liver disese -<1 1-<2 2-<3 3-<4 % SeHCAT retention Figure 2: Percentge SeHCAT retention in 21 ptients with cysticfibrosis x CN4 in CO) Cu 4- CD) ) LL k 3k 4r- 25F- 2K 15 F 1k FF o -o FBA 5 45 * Results o ) O FACAL FAT Fecl ft (g/24 h) 12 r k k 2 F- 4 1 CN 35 o to cm 3 _V 25 X _ 2 n 15 u _i 1 _ 5 ) X O - A N A N Figure 3: Feclft (FF) ndfecl bile cid (FBA) excretion in ptients with bnorml (A) nd norml (N) hydrogen breth tests Brs indicte men nd stndrd devition of the men tretment were compred using pired Student's t test A p vlue of < 5 ws considered significnt PATNTS The ptients with nd without liver disese were comprble with regrd to ge, sex, pncretic enzyme supplementtion, the prevlence of meconium ileus equivlent, nd nutritionl stte (Tble ) All ptients with liver disese hd dvnced disese with either fibrosis on liver biopsy exmintion or clinicl or endoscopicl evidence of portl hypertension Fecl ft excretion, expressed s g ft/g stool/24 hours in 'tients without liver disese (45 9 (8 6)x 1- ) ws similr to tht seen in ptients with liver disese (5- (l5 1)x1-O3) The coefficient of ft bsorption ws 81-3 (9 1)% nd 857 (3-9)% in the ptients with nd without liver disese respectively nd significntly lower thn in control subjects (97-1 ( 5)%; p<1; Tble ) FACAL BL ACD XCRTON Fecl bile cid excretion ws significntly higher in cystic fibrosis ptients without liver disese compred with control subjects (21-5 (2-4) nd 7-3 (1 2) [imol/kg/24 hours respectively; p<1) nd ptients with liver disese (7-9 (1-3) Vmol/kg/24 hours; p<1) Similr results were obtined when fecl bile cid losses were expressed s mg glycocholte equivlent bile cid/g stool/24 hoursx 1-2 (Tble ) There ws no correltion between fecl ft (g ft/24 hours) nd fecl bile cid ([imol bile cid/24 hours) excretion in the ptient group s whole or when ptients were strtified for the presence or bsence of liver disese (Fig 1) Similrly no correltion ws seen between fecl ft expressed s g ft/g stool/24 hours nd fecl bile cids expressed s mg bile cid glycocholte equivlent/g stool/24 hours (dt not shown) Three offour ptients with the highest fecl bile cid losses hd norml or ner norml ft excretions of 4 5, 6 9, nd 7-1 gl24 hours SeHCAT RTNTON The men percentge seven dy retention of SeHCAT in ptients with liver disese ws 3 (8-3)% nd comprble with tht in control subjects (36-8 (5-9)%; p=ns) n contrst men percentge seven dy retention in ptients without liver disese of 19-9 (3-8)% ws lower (p<5) thn in control subjects nd ptients with liver disese lthough the second did not rech sttisticl significnce (Tble ) Seven dy SeHCAT retention ws bnorml in eight (38%) of 21 cystic fibrosis ptients only one of whom hd liver disese SeCHAT retention in the remining five ptients with liver disese ws similr to, or greter thn, the vlue in control subjects (Fig 2) Gut: first published s 11136/gut on 1 August 1993 Downloded from on 7 June 218 by guest Protected by copyright

4 114 O'Brien, Mulchy, O'Broin, Csey, Burke, FitzGerld, Hegrty x C4 en 4_ ) Co co C) ) LL FF C cm 2 ' e _ 3 _ -[2 r = p = -6 correltion between pek, fter sucrose, breth hydrogen excretion nd percentge SeHCAT retention in the 12 ptients in whom both studies were performed (r= -2, p=ns; Fig 4) -c FFCT OF ANTMCROBAL TRATMNT 2 _ n four ptients with positive hydrogen breth tests treted with orl metronidzole (4 mg 1 * * * three times dily) for seven dys, fsting nd post - nj P sucrose breth hydrogen excretion decresed to norml vlues of less thn 12 ppm, which ws %SeHCAT retention ssocited with reduction in fecl ft excretion Figure 4: Correltion bettween breth hydrogen excretion nd in ll four ptients from 77 5 (8 4)x 1 3 to 57-7 % SeHCAT retention in 12 ptients with cysticfibrosis (15) g ft/g stool/24 hoursx 1-3 (p=ns) Fecl bile cid excretion decresed in three of four ptients from 15 2 (13c 1) mg to 84 5 (23 3) mg hile cid/g qtonl/24 hnircx 1-2 (n=ns: Fig S- BRATH HYDROGN XCRTON Sixteen (48 5%) of 33 cystic fibrosis ptients hd n incresed fsting breth hydrogen (three of five ptients with liver disese nd 13 of 28 ptients without liver disese; p=ns) (Tble ) with eight ptients hving pprecibly rised (>75 ppm) vlues (rnge ppm) The hydrogen breth test ws positive in 2 of 33 (66%) ptients nd no difference ws seen between the ptients with nd without liver disese (Tble ) Fsting breth hydrogen in control subjects ws less thn 12 ppm (rnge -11 ppm) nd did not increse fter sucrose given orlly RLATON BTWN BRATH HYDROGN XCRTON, FACAL FAT AND FACAL BL ACD LOSSS, AND SeHCAT RTNTON There ws no significnt difference in fecl ft excretion in ptients with positive nd negtive hydrogen breth test (59 3 (8 6)x 13 v 47 1 (18 9)x 1-3 g ft/g stool/24 hours respectively (p=ns) Similrly there ws no significnt difference in fecl bile cid excretion in ptients with positive nd negtive hydrogen breth test (167-1 (37) v (22 9) mg bile cid/g stool/24 hours respectively; p=ns; Fig 3) There ws no Before After Before After Figure 5: Fecl ft (FF) ndfecl bile cid (FBA) excretion in four ptients before nd fter seven dys tretment with orl metronidzole Breth hydrogen excretion hd returned to norml in llfour ptients FBA O N X w CD ) ) - ) C) CD ) 4 _v L% -T' N F,v, Discussion Severl studies hve shown tht fecl bile cid excretion is pprecibly rised in ptients with cystic fibrosis2a46 nd is comprble with tht seen in subjects who hve hd ilel resection2 The suggestion tht excess fecl bile cid losses in cystic fibrosis is relted to the presence of intrluminl unhydrolysed triglyceride,2 4 is bsed on: (1) close correltion between fecl bile cid nd fecl ft excretion2 4; (2) the finding tht improvements in ft digestion with pncretic enzyme supplementtion ws ssocited with concomitnt reduction in fecl bile cid losses2 i- 12; nd (3) substitution of dietry ft with medium chin triglycerides resulted in decrese in both fecl ft nd fecl bile cid excretion46 Not ll studies support direct link between ft mlbsorption nd fecl bile cid losses Thus correltion between fecl ft nd fecl bile cid excretion hs not been seen in ll studies356 Administrtion of sodium bicrbonte while reducing fecl ft excretion ws not ssocited with reduction in fecl bile cid losses nd in vitro studies hve filed to show n inhibitory effect of unhydrolysed triglycerides on ilel bile cid bsorption7 This study confirms previous findings tht fecl bile cid losses re incresed pprecibly in ptients with cystic fibrosis Severl findings re inconsistent with the theory tht n inhibitory effect of unhydrolysed ft on smll intestinl bile cid bsorption is mjor fctor responsible for fecl bile cid losses including: (1) the bsence of correltion between fecl ft excretion nd fecl bile cid loss; (2) the norml fecl bile cid losses in ptients with liver disese compred with the excessive losses in those without liver disese despite similr fecl ft excretion; nd (3) the finding tht ptients with ner norml ft excretion continue to lose lrge mounts of bile cids Thus fctors other thn the presence of intrluminl unhydrolysed triglycerides must be contributing to fecl bile cid loss in this group of ptients n vitro studies hve shown impirment of bile cid bsorption in the ilel mucos of ptients with cystic fibrosis9" A defect in ilel trnsport mechnisms is lso supported by in vivo findings suggesting selective mlbsorption of cholic cid, primry bile cid specificlly bsorbed by Gut: first published s 11136/gut on 1 August 1993 Downloded from on 7 June 218 by guest Protected by copyright

5 ntestinl bile cid mlbsorption in cysticfibrosis 1141 n ctive trnsport mechnism in the terminl ileum2" sing mrker perfusion technique, however, the uptke of turocholte nd glycocholte ws mesured in three infnts with cystic fibrosis nd ws noted to be similr to control subjects2' The results of this study re consistent with defect in the ilel trnsport of bile cids in ptients with cystic fibrosis with over third of such ptients retining significntly less rdiolbelled bile cids over seven dy period compred with control subjects Of prticulr interest were the findings tht the defect ws present predominntly in ptients without liver disese nd tht bile cid bsorption in ptients with liver disese ws comprble with control subjects This finding lso provides n explntion for the fct tht fecl bile cid excretion in ptients with liver disese is comprble with control subjects ntestinl motility disturbnces with prolonged intestinl trnsit times re well described in ptients with cystic fibrosis" nd my predispose to the development of smll bowel bcteril overgrowth, bcteril dehydroxyltion nd deconjugtion of bile cids, decresed bile slt solubility, diminished intestinl bile cid bsorption, nd excessive fecl bile cid loss Forty per cent of cystic fibrosis ptients in this series hd evidence of bcteril overgrowth bsed on fsting breth hydrogen excretion of greter thn 75 ppm fter prolonged fsting or positive hydrogen breth test 1819 The reduction in post sucrose breth hydrogen excretion, fecl ft, nd fecl bile cids fter ntibiotic tretment would suggest tht smll intestinl bcteril overgrowth contributes to mlbsorption in these ptients t is unlikely, however, tht bcteril overgrowth is mjor fctor determining the mlbsorbtion of ft nd bile cids s there ws no significnt difference in fecl ft nd fecl bile cid excretion in ptients with positive or negtive hydrogen breth test nd no correltion ws seen between breth hydrogen excretion nd SeHCAT retention The results of this study show tht: (1) excessive fecl bile cid losses in cystic fibrosis occurs lmost exclusively in ptients without liver disese of whom lmost 5% hve reduced retention of SeHCAT consistent with the presence of terminl ilel bile cid ctive trnsport defect; (2) fecl bile cid loss is unrelted to the presence of intrluminl ft; nd (3) bcteril overgrowth in these ptients plys minor prt in excessive fecl bile cid excretion 1 Prk RW, Grnd RJ Gstrointestinl mnifesttions of cystic fibrosis: A review Gstroenterology 1981; 81: Weber AM, Roy CC, Morin CL, Lslle R Mlbsorption of bile cids in children with cystic fibrosis NnglJMed 1973; 289: Goodchild MC, Murphy GM, Howell AM, Nutter SA, Anderson CM Aspects of bile cid metbolism in cystic fibrosis Arch Dis Child 1975; 5: Weber AM, Roy CC, Chrtrnd L, Lepge G, Dufour OL, Morin CL, et l Reltionship between bile cid mlbsorption nd pncretic insufficiency in cystic fibrosis Gut 1976; 17: Wtkins JB, Tercyk AM, Szczepnik P, Klein PD Bile slt kinetics in cystic fibrosis: influence of pncretic enzyme replcement Gstroenterology 1977; 73: Smlley CA, Brown GA, Prkes MT, Tese H, Brookes V, Anderson CM Reduction of bile cid loss in cystic fibrosis by dietry mens Arch Dis Child 1978; 53: Hrries JT, Muller DPR, Mc Collum JPK ntestinl bile slts in cystic fibrosis Arch Dis Child 1979; 54: Weber AM, Roy CC Bile cid metbolism in children with cystic fibrosis Act PeditrScnd 1985; suppl 317: Fondcro JD, Heubi J, Kellogg FW ntestinl bile cid mlbsorption in cystic fibrosis: primry mucosl cell defect PeditrRes 1982; 16: De Rooij FWM, Vn den Berg JWO, Sinsppel M, Bosmn- Jcobs P, Touw-Blommesteiin AC Bile cid mlbsorption in cystic fibrosis; membrne vesicles, tool for reveling the role of the ilel brush border membrne Act Peditr Scnd 1983; suppl 317: Bli A, Stbleforth D, Asquith P Prolonged smll intestinl trnsit time in cystic fibrosis BMJ 1983; 287: Roller RJ, Kern F Miniml bile cid mlbsorption nd norml bile cid breth tests in cystic fibrosis nd cquired pncretic insufficiency Gstroenterology 1977; 72: Deprtment of Helth nd Socil Security Recommended dily mounts offood energy nd nutrients for groups ofpeople in the K (revision) Report No 15 London: HMSO, Vn de KmerJH, ten Bokkel Juinink H, Weijers HA A rpid method for the determintion of ft in feces J Biol Chem 1949; 177: De Wel J, Rymkers C, ndemn HJ Simplified quntittive determintion of totl fecl bile cids Clin Chim Act 1977; 79: Boyd GS, Merrick MV, Monks R, Thoms L Se-75-lbelled bile cid nlogs, new rdiophrmceuticls for investigting the enteroheptic circultion J Nucl Med 1981; 22: Nyhlin H, Merrick MV, stwood MA, Brydon WG vlution of ilel function using 23-selen-25-homoturocholte, y-lbelled conjugted bile cid Gstroenterology 1983; 84: Metz G, Cssull MA, Drsr BS, Jenkins DJA, Blendis LM Breth hydrogen test for smll intestinl bcteril colonistion Lncet 1976; i: Kerlin P, Wong L Breth hydrogen testing in bcteril overgrowth of the smll intestine Gstroenterology 1988; 95: Colombo C, Rod A, Rod R, Piceni Serini L, Breg A, Fugzz R, et l Bile cid mlbsorption in cystic fibrosis with nd without pncretic insufficiency J Peditr Gstroenterol Nutr 1984; 3: Thompson GN, Dvidson GP n vivo vile cid uptke from terminl ileum in cystic fibrosis Peditr Res 1988; 23: Northfield TC, Drsr BS, Wright JT Vlue of smll intestinl bile cid nlysis in the dignosis of the stgnnt loop syndrome Gut 1973; 14: Lewis R, Gorbch S Modifiction of bile slts by intestinl bcteri Arch ntern Med 1972; 13: Gut: first published s 11136/gut on 1 August 1993 Downloded from on 7 June 218 by guest Protected by copyright