REVIEW ARTICLE

Lactulose, Disaccharides andColonic FloraClinical Consequences

Mette Rye Clausen and PerBrebech Mortensen

Department of Medicine CA, Division of Gastroenterology, Rigshospitalet,Universi ty of Copenhagen, Copenhagen, Denmark

Contents

Drug s 1997 Ju n: 53 (6) : 930-9420012-6667/97/rJ:XJO-O<I3O/ S13.00/0

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Summary .1. Dietary Carbohydrate .

1.1 Lactulose . . . . .2. Colonic Fermentation and Producti on of Short-Chain Fatty Acids (SCFA)

2.1 Fermentation of Lactulose .3. Lactulose in the Management of Constipation . . . . . . . .

3.1 Colonic Compensation in Car bohydrate Malabsorption3.2 Fermentation Capac ity Threshold : Ind ividual Variability .3.3 Does Lactulose Exert Its La xa tive Effec t Through the Osmotic Activity of

Unferme nted Carbohydrate? .3.4 Capac ity of the Colon to Absorb Fluid .3.5 Possible Me chanisms of Action of Lactulose in the Treatment of Constipation.

4. Lac tulose in the Management of Hepatic Encephalopathy . . . . . . . . . . . .4.1 Effects of Lac tulose on Ammonia and Nitrogen Metabolism . . . . . . . . . .4.2 Role of Short- and Medium-Chain Fatty Acids in Hepatic Enc ephalopathy .4.3 Effect of Lactulose on Colon ic SCFA Produc tion in Hepatic Encephalopathy4.4 Possible Mechanisms of Action of Lactulose in the Treatment of

Hepatic Encephalopathy5. Conc lusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

930931931931932933933934

935936936937937938939

940940

Summary Lactu lose is one of the mos t freq uen tly utilised age nts in the treatment ofconstipation and hepatic ence pha lopat hy because of its efficacy and good safe typrofile. The key to understanding the possible modes of action by which lactuloseac hieves its therapeutic effects in these diso rders lies in certain pharmaco logicalphe nomena: (a) lactu lose is a sy nthetic disaccharide that does not occur naturally;(b) there is no disaccharidase on the microvi llus membrane of enterocytes in thehuman small inte sti ne that hydrolyses lactulose; and (c) lactulose is not absorbedfrom the small intestine. Thus, the primary site of action is the colon in whichlactulose is readi ly fermented by the co lonic bacterial tlora with the produ ctionof short-chain fatty acid s and various gases. T he purpose of this review is to focu son some pertinent basic aspects of the clinica l pharmacology of lactulose and todiscu ss the possible mec hanisms by which lactulose benefits patients with co n­stipation and hepatic encephalopat hy.

Disaccharides and Colonic Flora 931

1.Dietary Carbohydrate

Dietary carbohydrates may be divided intomonosaccharides, disaccharides, oligosaccharidesand polysaccharides. Their physiological proper­ties and health benefits depend on the site, rate andextent of their digestion or fermentation in the hu­man gastrointestinal tract. The polysaccharidefraction of plant cell walls (dietary fibre) and someforms of starch (resistant starch) are resistant tohydrolysis in the small intestine. These carbohy­drate polymers as well as indigestible oligosaccha­rides, e.g. stacchyose and raffinose, enter the colonthrough the ileocaecal valve to be fermented by thecolonic bacterial flora. Monosaccharide and disac­charide sugars are absorbed as they pass throughthe healthy small intestine and only become avail­able to the colonic flora as a consequence of defi­ciencies in the transport system, or, more usually,specific disaccharidase deficiencies, e.g. lactasedeficiency. Physiological carbohydrate malabsorp­tion, that is, the fermentable carbohydrate enteringthe colon in healthy individuals, is in the range of30-60 g/day in Western communities.l!l This loadis normally fermented by the vast numbers of co­lonic bacteria.

1.1 Lactulose

Lactulose is a synthetic disaccharide composedof the monosaccharides galactose and fructose [p­( 1-4)-galactosido-fructose] . The disaccharidasesthat split naturally occurring disaccharides intotheir hexose moieties do not include a lactulase,and lactulose is not metabolised or absorbed in the

human small intestine.Pv' Once in the caecum,lactulose is a fully fermentable carbohydrate.Lactulose is widely considered to be an effectiveagent in the management of constipation and he­patic encephalopathy. It is the purpose of this re­view to discuss the interaction of lactulose with thebacterial flora of the colon and the possible modesof action by which it achieves its therapeutic effectsin patients with constipation and hepatic encepha­lopathy. The review deals almost exclusively withlactulose. The principles expressed, however, areapplicable to any malabsorbed and fermentable di­saccharide, e.g. lactitol, a disaccharide analogue oflactulose for which there is also no disaccharidaseon the microvillus membrane of enterocytes, orlactose when it is administered to lactase-deficientindividuals.

2. Colonic Fermentation and ProductionofShort-Chain Fatty Acids (SCFA)

Fermentation, the process whereby the micro­bial population that inhabits the human colonbreaks down carbohydrates in order to obtain en­ergy for maintenance of cellular function andgrowth, is an important component of normalcolonic activity (fig . I) . Short-chain fatty acids(SCFA) and the gases H2, CO 2 and, in some indi­viduals, CH4, are the principal end products of car ­bohydrate fermentation.l!' The major SCFA foundin the human colon are the C2 (acetate), C3 (pro­pionate) and C4 (butyrate) members of the ali ­phatic monocarboxylic acid series. Formate (C I) ,valerate (C5), hexanoate (C6), and the branched-

Dietary mono·, di- and oligosaccharides

SCFA,H2,C02,CH.andincreased bacterial mass

BacterialenzymesIPolysaccharides 1- - - - -- ICarbohydrates Ir-- - -

Fig. 1. Bacterial fermentation in the human colon . Abbrevialion: SCFA = short-chain fatty acids .

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chain fatty acids isobutyrate (iC4) and isovalerate(iC5) , whi ch are produced during amino acid fer­ment ation ,14's1are also present in the co lon, thoughin smaller quantities. Oth er orga nic ac ids such aslactate and succ inate are ferment ati on intermedi­ates. Th ey can be further metaboli sed to SC FA, anddo not usually accumulate to any extent, exceptduring rapid carbohydrate breakd own. P"!

Th e SCFA are weak acid s and their pKa valuesare very similar, rangin g from 4.76 to 4 .87 . Thu s,more than 95% of the SCFA are present in theirdi ssociated form at the phy siological pH of the co­lon (pH 6-8) . Total co ncentrations of SCFA are lowin the sma ll intestine, but in the co lon and faecesSCFAco nstitute the predominant ani ons at concen­tration s ranging from about 80 to 130 mmol/Lp ·IOIConcentrati ons are highest in the caecum, wheresubstra te avai lability is grea tes t, and fa ll progres­sive ly towards the dista l co lon. By co ntras t, pH islowest in the right colon and rises in the distalbowel .l?' SC FA are av idly abso rbed by the co lonicepithe lium,II I.1 21 and used as a source of energy,e ither locall y (co lonic mucosa)113. 151 or syste mi­ca lly (l iver, peripheral tissues).' 161 In the colon, ab­sorpt ion of SCFA is accompanied by luminal bicar ­bon ate acc umulatio n and inc reased sodium andwate r absorption.t'I -P!Thu s, the micro bia l processco nve rts unabsorb able materi al to rapidly absorbedSCFA, thereby redu cing the effective osmo tic pres­sure of the co lonic co ntents, enhanci ng water andelectrol yte abso rption, and sa lvag ing calo rieswhi ch wo uld otherwise be lost in the faeca l strea m.

2.1 Fermentation of Lactu lose

Lactul ose, after arriving in the colon, is digestedby bacteri al disaccharidases and metaboli sed to or­ga nic aci ds, mainl y acetate and lactate , H2 andC02.1 61 A variety of studies have show n that lactu­lose is usuall y vigorously fermented . In an ill vitroex pe rime nt using human faecal homogen ates,Vince et aLI171showed that co mplete fermen tatio nof 10 giL (30 mmol/L ) of lactul ose occurred within6 hours. By use of a similar tech nique, Mortensenet aLII X.191 showed tha t the total product ion ofSCFA in faeca l homoge nates was increased 2- to

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Clausell & Mor!('//s('//

3-fo ld by the additio n of 100 mmol/L lactulose orits mon osacch ari de co ns tituents, ga lac tose andfructose, during inc ubation for 6 hours , secondaryto an iso lated 4- to 6-fo ld increase in the synthes isof acetate. In patient s undergoing elective chole­cystectomy, caecal insti lla tio n of lactulose ca usedan immediate inc rea se in por tal plasma SCFAco nce ntrations, principally acetate; peak co ncen­trations were achieve d in 15 to 45 minutes, co n­firming efficient fermen tatio n of lactulose and ab­sorption of the resultant SCFAP ol

Th e various gases ge nerated in the co lon are ei­ther absorbed and ex pired in breath or expelled asflatu s, and excess gas production may ca use bor ­borygm i and flatul ence. Sin ce H2 produced in thehuman bod y deri ves entire ly from bacter ial fer­ment ation of nonabsorbed carb oh ydrate, brea th H2

exc retion in the abse nce of sma ll intes tinal bacte­rial ove rgrowth ca n be used as a marker of carbo­hydrate rnalabsorpt ion .F! ' Th e extent of ma lab­sorption may be quantified by co mparing breath H2

excretion following a test dose of lactulose withtha t after ingestion of a different carbohydrate.l->'

Fermentation of a readily fermen tab le carbohy­drate result s in acidification of co lonic co ntent s.Using a pH-sensitive rad iotelem etry de vice, Bownet aL/231 showed that lactul ose 30 to 40g da ily de­creased the pH of the right co lon fro m contro l lev­els of 6.0 to 4.8 5. As the intes tinal co ntent reachedthe left co lon and rectum, the median pH rose,probab ly as a res ult of SCFA absorpt ion and bicar ­bonate sec retion. Th e effect of lactulose on faeca lpH depend s on the dose employed, and the drop inpH is usually maint ain ed throughout the co lon andthe stool when larger doses of lactul ose are ad min­istered.124.261

Alth ough co ns istent cha nges in the relat ive pro ­por tion s or in the abso lute numbers of differe ntbacterial species have been difficul t to ide ntify inpat ient s treated with lactul ose,1 27-291this co mpou nddoes appea r to have a significant effect on the me­taboli c ac tivities of the microb es. In healthy volun­teers, faeca l levels of ~-galactosidase activity in­creased significantly after an 8-da y period o f anon diar rhoeogeni c dose of lactu lose (20g twice

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Disacchari des and Colonic Flora

daily j.!'" Co mpared with day I , caecal co ntentssampled on day 8 afte r lactul ose administ ration ex­hibit ed a mar ked fall in pH, a faster disappearanceof lactulose and its co nstitutive hexoses, and in­creased co ncentrations of SCFA and lactate.l'" Theco lonic microflora therefore are able to adapt toferment lactul ose, and the more efficie nt bacteri alfermentation of lactul ose mod ifies the diarrhoeaindu ced by a larger load of this sugar.P'!'

Th e co lonic bacter ia use ferme ntable carbohy­drate, e.g . lactul ose, as a so urce of ene rgy, thu sprom oting their growth and multipl ication. P!' It isbel ieved that bacteri al growth ass imilates the am­moni a produ ced by degradation and putrefactionof ingested prot ein s as a source of nitrogen , andfaeca l nitrogen exc retion increas es 2- to 4-fo ld af­ter lactul ose administration.tv-P!

3. Lactulose in the Managementof Constipation

Lactul ose is frequently used as an effective lax­ative in the management of constipation.P"! Basedon the absence of its respecti ve disaccharidase, therationale for the use of lactulose as a laxative wasto indu ce disacch aride malab sorption, a we llknown cause of diarrh oea. In spite of the freq uencyand importan ce of ca rbo hydrate-i nduce d diar ­rhoea, its pathophysiology is not full y understood .Until re lative ly rece ntly, SC FA were thought to bepoorly abso rbed and to functi on as an irrit ating andos motic force stimula ting intes tina l motilit y andimp eding co lonic water and elec tro lyte absorp­tion .135.3xl Early work on carbohydrate malabsorp­tion therefo re impli cated bacter ial fermentation asthe prim ary mechani sm for diarrhoea in disaccha­ride malabsorption (' ferme ntative diarrhoea ' ). Th estro ng co rre lation between faecal water output andoutput of SCFA135.371 was thought to incriminateSCFA in the path ogenesis of diarrhoea. As co lonicSCFA levels remain more or less co nstant despitedietary changes, any fac tor increasing stool we ightwill, however, increase their output. Later in vivostudies of intes tinal SCFA abso rption have consis­tent ly de mo nstrated efficient absorption of SCFAfrom the human colon.' I 1.1 21 Th is absorption mark-

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933

edly enha nces net sodi um and water abso rptio nand bicarb onate secretion into the lumen. Thu s, theintracolonic fer mentation of nonabsorbed suga rsinto readily absorbable SCFA reduces the osmoticload , and suppresses or mit igates the diarrhoeawh ich would have resulted from unm odified ilealoutput.

3.1 Colonic Compensation inCarbohydrate Ma labsorption

Th e protect ive role of coloni c fermentation inreducing the severity of carbohydrate-induced diar­rhoea has been demonstr ated in studies co mparingthe output of faecal water in response to a non­fe rme ntable os mo tic load with a load of ferm ent­able carbohydrate. Hammer et al.1391co mpared thediarrh oea res ulting fro m increasin g iso -os mo larloads of the nonabsorbable, nonferment able andelec trically neut ral co mpound polyeth ylene glyco l(PE G) and lactulose in healthy individuals. In­creasing osmotic loads of PEG caused a near-li nearincrease in stool wa ter output. At any load,lac tu lose ind uced less diarrhoea than did PEG.With low (45 g/day) or moderate (95 g/day ) dosesof lact ulose, stool water losses were redu ced by asmuch as 600 g/day (co mpared with equimo lar os­motic loads of PEG ). As lactulose doses of >45g/day were ingested, faecal ca rbohydrate exc retionrose progressively, thereb y contributing more andmore to the osmotic dr iving force for diarrh oea.With the largest dose of lactul ose (125 g/day) thedifferen ce between lactulose- and PEG-induceddiarrh oea markedly decreased . In lactulose- inducedd iarrhoea, daily stoo l collections co nta ined anaverage of I, 12 and 45g of carbohyd rate when theparticipant s were ingesting 45 , 95 and 125g oflactul ose/d ay, respecti vely, indi catin g a maximumca pacity of the co lonic bacteria to met aboli selactulose of approximately 80 g/day.' 39I

Saunders and Wiggi nsl' ! obtained dose-responsecurves fo r mann itol (a poorly absorbed sugar alco ­hol ), raffi nose, lactulose and magnesium sulfate inrelation to faecal water ou tput over 48 hours afte rthe dose of test substance. With magnesium sulfatethere was an immediate inc rease in faecal output,

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whereas a lag period was observed for the non­absorbed sugars. When an increase in faecal wateroccurred after ingestion of mannitol, lactulose orraffinose, the sugar or its constitutive hexoses ap­peared in the stools. The dose-response experi­ments indicated that the colonic flora can normallyconvert 40 to 60g of single doses of carbohydrateto SCFA without the individual experiencing diar­rhoea.I"

3.2 Fermentation Capacity Threshold:Individual Variability

The human colon is obviously capable of re­moving appreciable amounts offermentable carbo­hydrates from colonic contents, even in patientswith malabsorbed carbohydrate.Ue'" If, however,the fermentative capacity of the colonic microflorais exceeded, unmodified and osmotically activesugars may produce an osmotic diarrhoea. The re­sponse threshold when a given amount of carbohy­drate is malabsorbed differs among individuals, Inthe study by Saunders and Wiggins.U' one partici­pant tolerated a 73 mmol (25g) dose of lactulosewhereas another tolerated 176 mmol (60g) beforefaecal water output rose above 400 ml/48 hours andtest carbohydrate appeared in the stool. Similarly,doses of 120 mmol (22g) and 350 mmol (64g) ofmannitol were tolerated by different participants.

The individual variability may, at least in part,be explained by differences in the fermentation ca­pacity of the bacterial flora. Individuals with a lim­ited fermentation capacity or a high dependence onthe existing capacity for colonic carbohydrate deg­radation might be especially susceptible to an in­creased carbohydrate load. A similar situation mayapply to the development of microbial fermenta­tion in newborn animals. Argenzio et al.1401 pro­duced carbohydrate malabsorption by administra­tion of corona virus to newborn pigs. This resultedin diarrhoea in 3-day-old pigs, with high concen­trations of carbohydrate and low concentrations ofSCFA in colonic contents. Pigs 3 weeks of ageshowed no diarrhoea, with negligible amounts ofcarbohydrate and normal levels of SCFA in coloniccontents, indicating that the more mature micro-

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Clausell & Mortellsell

flora in these older piglets were capable offerment­ing the osmotic load to SCFA, which could then berapidly absorbed from the colonic contents. Oncethe microbial process is well established, pro­longed ingestion of carbohydrate results in an im­proved colonic fermentation capacity.l'v'"

The higher capacity to ferment carbohydratesmay be a result of enzymatic induction in existingrnicro-organisms!''! and/or an alteration in micro­bial populations.lv-'!' Flourie et al.1301 studiedhealthy volunteers for 2 test periods, at the begin­ning of which they ingested a diarrhoeogenic load(60g) of lactulose; the 2 periods were separated bya lactulose feeding period of 8 days, during whicha nondiarrhoeogenic load (20g) of lactulose wastaken twice daily. Stool weight and frequency, andfaecal outputs of carbohydrates after the ingestionof lactulose 60g, dropped significantly after thelactulose maintenance period (20g twice daily for8 days), indicating that the colonic flora can adaptto a nondiarrhoeogenic load of lactulose, and thatthis adaptation has a beneficial effect on the diar­rhoea induced by a larger load of this sugar.

Similarly, Launiala!"!' reported on a 3-weekperiod during which an infant with congenital lac­tose malabsorption was maintained on a lactose­containing diet. In comparison with the first day oftreatment, continued treatment resulted in a de­creased stool volume and disaccharide output, anda sharp rise in faecal lactate concentration. No ad­aptation occurred in the small intestine.H!'

Hypothetically, regular consumption of carbo­hydrates malabsorbed in the small bowel may re­sult in a more efficient colonic carbohydratefermentation and an increased response thresholdwhen a given amount of carbohydrate is mal­absorbed. In addition to differences in colonic bac­terial fermentation capacity, variations among in­dividuals in the buffering capability of the colonmay contribute to individual differences in the re­sponse to identical amounts of nonabsorbable car­bohydrates. It is known that caecal pH decreaseseven with the amounts of unabsorbed carbohydratenormally entering the colon .F" Furthermore, pa­tients with severe carbohydrate malabsorption, ei-

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Disaccharides and Colonic Flora 935

::J150

::,0E.s 1002l!!"0>- 50JC::.0

of?IIIU 0

8

7

J: 60-

5

4 )2280)2100

1500)2300)1678

.EOJ

.~

~8: 500

i 1000

~

o 20 40 80 160 320 0 20 40 80 160 320

Lactulose (g/day)

Fig. 2. Faecal weight,pH and carbohydrateconcentrationin faeces of 12 individualstaking increasingdoses of lactulose. The resultshave been divided in accordancewith the response in faecal output to low doses of lactulose (from Holtug et al.,126] with permission).

ther due to disaccharidase deficiency or due to in­gestion of excessive amounts of lactulose, have de­creased faecal pH in the range of 4 to 5.124,26,35]

This decrease in pH is sufficient to inhibit bac­terial fermentation and SCFA production as shownin vivo and in vitro.126,42,43 j In subjects with a re­stricted colonic buffering system, the tolerance ofcarbohydrate malabsorption may be decreased asthe low pH decreases fermentation leading to ac­cumulation of undigested sugars and osmotic diar­rhoea early on in the process .

3.3 Does Lactulose Exert ItsLaxative EffectThrough the Osmotic Activity ofUnfermented Carbohydrate?

Many physicians believe that the change instool output in the diarrhoea of carbohydrate mal­absorption is due to the osmotic effect of malab­sorbed and nonfermented sugars. This assumptionseems to be supported by the studies mentionedabove (sections 3.1 and 3.2) in which diarrhoeaensued when carbohydrate appeared in the stools.The study by Holtug et aI.,126 1however, queries this

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assumption. Healthy individuals were given lactu­lose twice daily for 3 consecutive days in each ex­perimental period. Doses were doubled (20, 40,80,160 and 320 g/day) from each period to the next,with the end-point being diarrhoea in excess of1000 g/day. Faecal output responded differentlyamong individuals, and 2 types of behaviour wereidentified (fig . 2).

In accordance with the interpretation that carbo­hydrate-induced diarrhoea is due to the osmotic ef­fect of nonfermented mal absorbed sugars, diar­rhoea occurred suddenly in six of 12 individuals inassociation with the appearance of carbohydrate infaeces . In the 6 other subjects, however, faecal out­put gradually increased with increasing doses oflactulose and diarrhoea occurred before the appear­ance of faecal carbohydrates.P''! How does unab­sorbed carbohydrate cause diarrhoea in thosecases?

3.4 Capacity of the Colon to Absorb Fluid

The mechanism of action of lactulose as a laxa­tive is probably multifactorial, involving effects onboth the colon and the small bowel. Under normalcircumstances, about 1500ml of fluid is estimatedto enter the colon each day.14411ndisaccharide mal­absorption an increased volume of fluid is retainedin the lumen of the small intestine by the osmoticeffect of disaccharide.141,451 Analysis of distal ilealfluid collected during the passage of a lactose mealin lactase-deficient people and a lactulose load inhealthy people indicates that about two-thirds ofthe osmotic load entering the colon consists ofendogenous electrolytes.130,41,45] Thus, the waterload delivered to the colon is about 3 times thatcalculated to be osmotically held by the non­absorbed sugar.

A logical extension of the above observations isto ask what the colon can accomplish under stress.In fact, the colon has a surprisingly large capacityto adapt to fluid overload. When the healthy humancolon was subjected to a slow, continuous infusionof isotonic fluid (1.4 to 2.8 ml/min), net absorptionof water increased markedly, up to 5 to 6 L/day.1461

The rate and pattern of t1uid entry are , however, of

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Clausen & Mortensen

major importance. Rapid infusion (8.3 ml/min) ofa single bolus of 250ml of t1uid did not influencefaecal output whereas 500ml delivered at the samerate overwhelmed the absorptive capacity of thecolon and produced liquid stools.U''!In healthy hu­man volunteers, Chauve et al.1471investigated pres­sure recordings in the right , transverse and left co­lon, while isotonic saline was continuously infusedin the caecum. The data obtained indicated thatonce a certain volume of content is reached in theproximal part of the colon, it contracts and propelsits content.l''?' which may explain the different co­lonic responses comparing slow continuous andrapid bolus infusions of t1uid into the caccum .lv '

The extra volume load to the colon due tolactulose can be estimated to be 1.65L at a lactuloseintake of 60g,130,41,451and the sudden arrival in thecaecum of this considerable amount of ileal dis­charge might lead to colonic 'decompensation ' andprompt colonic evacuation.

3.5 Possible Mechanisms of Action ofLactulose in the Treatment of Constipation

A single primary mechanism for the laxative ef­fect of lactulose cannot be determined because ofmultiple possible effects . Most likely , the laxativeeffect of lactulose results from the combination of:• water retention in the small intestine through the

osmotic activity of the unabsorbed disaccha­ride; and

• interference with net t1uid absorption in the co­lon due to the osmotic effect of malabsorbed andintact sugars when the bacterial fermentationcapacity is exceeded.Whether or not the laxative effect of lactulose is

accomplished is probably just a matter of dose . Itis, however, important to realise that the responsethreshold when lactulose is prescribed differsamong individuals (fig . I) . A gradual increase infaecal output with increasing amounts of lactuloseoccurs in some individuals, while others suddenlyrespond with severe diarrhoea.P'" Unfortunately, itis not possible to predict the response of a givenindividual, and firm guidelines for dosage recom­mendations are impossible.

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Disaccharides and Colonic Flora

4. Lactulose in the Management ofHepatic Encephalopathy

Lactulose has been successfully used in thetreatment of hepatic encephalopathy ever sincethe pioneering experiments of Bircher et al. in1966.'241 The exact mechanisms whereby lactuloseexerts its beneficial effect on hepatic encephalop­athy are not fully understood, but several hypoth­eses have been suggested.

Hepatic encephalopathy is a complex neuropsy­chiatric syndrome that appears to be characterisedpredominantly by augmented neuronal inhibition.The syndrome is associated with hepatocellularfailure, increased portal-systemic shunting ofblood and multiple metabolic changes, and is gen­erally considered to be a potentially reversible me­tabolic encephalopathy. The precise pathogeneticmechanism responsible for the CNS dysfunctionremains to be determined.

Products of bacterial metabolism in the colon,which are normally absorbed and extracted by theliver, tend to accumulate in the peripheral blood ofpatients with liver disease either because the dis­eased liver is unable to remove these compoundsfrom the portal blood perfusing it, or because por­tal hypertension has led to the development of ve­nous collaterals which transmit portal blood di­rectly into the systemic circulation. If one or moreof these metabolites can cross the blood-brain bar­rier and promote neural inhibition, they may con­tribute to hepatic encephalopathy. Despite decadesof research endeavour, the nature of the toxic, gut­derived, substances defies identification. Threecandidate toxins seem likely pathogenetic factorsbecause they are present to excess in patients withliver failure and cause coma experimentally in ani­mals. These are ammonia, SCFA and medium-chainfatty acids (MCFA), and mercaptans; of these, am­monia probably plays the most central role.'48I

4.1 Effects of Lactulose on Ammonia andNitrogen Metabolism

Ammonia occupies a central position in nitrogenmetabolism in the colon, both as an end-product of

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bacterial metabolism of amino acids , peptides andproteins.P?' and as the simplest nitrogenous com­pound which can be used by bacteria as a startingmaterial in the synthesis of their own nitrogenousconstituents. In the absence of active colonic fer­mentation most of the ammonia formed is ab­sorbed to be converted to urea in the liver.

When lactulose was first used in the treatmentof hepatic encephalopathy, it was presumed thatthe colonic acidification favoured the growth ofacid-tolerant lactobacilli and other acidophilic, fer­mentative bacteria and reduced the growth ofacidophobic, proteolytic bacteria responsible forammonia formation .P'! However, quantitativestudies failed to confirm this rearrangement of gutf1ora.127,281 Alternatively, luminal acidificationwould reduce the proportion of ammonia availablefor reabsorption by passive nonionic diffusion byincreasing the ratio of ionised to unionised ammo­nia, thereby enhancing the faecal excretion of am­monia.P'!' Attempts to demonstrate increases instool ammonia caused by lactulose administrationhave failed,151 ,521 except when excessive amountsof lactulose (>80 g/day) have been given.F'l ln thatcase, stool ammonia increases approximately 3­fold .1331The main point is, however, that ammoniaconstitutes only a small percentage (3 to 5%) oftotal faecal nitrogen. The debate on whether or notlactulose increases faecal excretion of ammonia istherefore of minor importance in the context of to­tal nitrogen excretion. Of more importance for fae­cal nitrogen clearance are other sources of nitro­gen, constituting about 95% of total stool nitrogen.

By use of an anaerobic faecal incubation sys­tem, Vince et al. I171demonstrated that net genera­tion of ammonia by faecal bacteria can be con­verted to net utilisation of ammonia by theprovision of a fermentable source of energy, e.g.lactulose, ammonia disappearing from the incuba­tion system. The results may be explained by acombination of factors: (a) the availability of areadily fermentable substrate may encourage bac­terial proliferation and assimilation of ammonia asa nitrogen source;' 17,31 I (b) preferential use oflactulose as a carbon and energy source may exert

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a sparing effect on the metabolism of both exoge­nous and endogenous aminated compounds with asubsequent decrease in the generation of ammoniaby colonic bacteria;117, 191 and, (c) low pH valuessuch as are induced in the colon by lactulose maybring about a general reduction in bacterial meta­bolism, including that of ammonia-producing bac­teria.l 17,19,26,421 If, in the presence of lactulose, in­corporation of ammonia into bacterial protein isstimulated, faecal nitrogen excretion should in­crease and hepatic urea production and total bodyurea pool should decrease during administration oflactulose.

This is exactly what Weber l321and Mortensen'Vlhave shown. Administration of lactulose caused a2- to 4-fold increase in faecal nitrogen content inpatients with cirrhosisl321and in healthy individu­als,1331 and the increase in nitrogen excretion wasaccompanied by a significant reduction in the ureaproduction rate leading to a reduction in the totalbody urea pool.1321Using recently developed tech­niques that permit quantitative separation of faecalsolids into bacterial, soluble and fibre fractions,Weber et al.1531analysed the effects of lactulose onthe compartmentalisation of faecal nitrogen. In pa­tients with cirrhosis, administration of lactulose(56 ± 6 g/day) caused a marked increase in both thesolid weight and nitrogen content of the bacterialand soluble fractions of stool ; lactulose administra­tion increased nitrogen excretion in the bacterialand soluble fractions by 165 and 135%, respec­tively. The major increment in nitrogen content ofthe bacterial fraction indicated that lactulose stim­ulated bacterial growth and multiplication signifi­cantly, and thereby increased the incorporation ofnitrogenous compounds such as ammonia into bac­terial protein.

The increase in faecal soluble nitrogen may beexplained by reduced bacterial catabolism of ni­trogenous compounds to absorbable metabolites,e.g. ammonia, due to: (a) the introduction of a car­bohydrate which is preferentially used as a carbonand energy source;117,191 (b) an increase in thehydrogen ion concentration which may bringabout a general reduction in bacterial metabo-

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Clausen & Mortensen

lism;117,19,26,421 or (c) both. A direct effect of lac­tulose in reducing the colonic transit time may alsobe a factor contributing to an increase in faecal sol­uble nitrogen.

4,2 Role of Short- and Medium-Chain FattyAcids in Hepatic Encephalopathy

The suggestion that SCFA and MCFA may playa role in the pathogenesis of hepatic encephalopa­thy is mainly based on animal experiments. Sam­son et aI.i541 investigated the narcotic action ofSCFA (acetate, propionate, butyrate, valerate andhexanoate) and MCFA (heptanoate and octanoate)in experimental animals , Intravenous or intra­peritoneal injection of the sodium salt s of theseacids produced a reversible coma with a definiterelationship between the amount of the fatty acidwhich would produce unconsciousness and thecarbon length of the compound; i.e . the longer thecarbon chain, the more potent the encephalopathiceffect, acetate being almost nontoxic.P'l

In a subsequent experiment, White and Sam­son l551demonstrated that intravenous injection ofpropionate, butyrate, valerate and hexanoate im­mediately induced electroencephalographic (EEG)changes from a resting type to one of sleep in un­anaesthetised rabbits . During these EEG alter­ations, overt signs of drowsiness or sleep alwaysoccurred and the typical 'alert' EEG responses tonociceptive and auditory stimuli were diminishedor absent. Again , the longer the carbon chain, themore potent the effect. In rats , the rate of blood­brain barrier penetration of straight-chain saturatedmonocarboxylic acids has also been shown to in­crease with chain length and is virtually completeat lengths greater than that of hexanoate (C6).1561

In humans, octanoate has been shown to cross theblood-brain barrier in both normal individuals andpatients with cirrhosis.lV'

The mechanisms by which SCFA and MCFA in­terfere with CNS functions are not entirely clear.In vitro and in vivo stud ies have shown that SCFAand MCFA inhibit cerebral Na+,K+-ATPase activ­ity,15X,591and, as for the narcotic potency, the inhib­itory capacity increases with increasing chain

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Disaccharides and Colonic Flora

length.P'" The con sequences of inhibiting this en­zyme would include an increase in intracellular so­dium and possibl y impaired neurotransmi ssion.

Muto and Takahashi t'v ' were the first to sugges ta role of SCFA in the pathogenesis of hepatic en ­cephalopathy. In patients with hep ati c coma, pla s­ma level s of SCFA of 4- to 6-carbon length wereincreased 3- to 4-fold compared with controls andpatients with other kind s of coma. Significantlyelevated levels of SCFA in peripheral venous bloodof patients with fulminant hepatic failure and por­tal systemic encephalopathy have been confirmedrecently. Lai et al.1611investigated 6 patients withfulminant hepatic failure due to paracetamol (aceta­minophen) intoxication and hepatitis. All patientswere in grade IV coma. Pla sma levels of SCFAwere significantly elevated in patients with en­cephalopathy (2034 ± 11341lmo1/L; mean ±2 SO )compared with 10 healthy controls ( 1113 ± 662um ol/L), but a correlation between SCFA con cen­trations and the clinical course could not be dem­onstrated.

Clausen et al.1621inve stigated 32 patients withcirrhosis, 15 patients with and 17 patients withouthepatic ence phalopathy, and II health y indi vidu­als. Plasma concentrations of SCFA were signifi­cantly elevated in patients with hepatic encepha­lopathy (362 ±831lmo1/L; mean ±SEM) comparedwith patients without encephalopathy ( 178 ± 57umol/L) and healthy controls (60 ± 8IlmoI/L). Re­petitive sampling from the encephalopathic pa­tients showed no relationship between SCFA con­centrations and the grade of encephalopathy.I '<'

In comparison with the encephalopathy asso­ciated with inborn errors of organic acid metabo­lism, el evated levels of SCFA in patients withhepatic encephalopathy are modest. Massive ele­vations of propionate are found in severe and fatalca ses of propionic acidaemias (5400 to 38 000IlmoI/L ),1 63-651 and levels of isovalerate in therang e of 340 to 2990 umol/L are associ ated withstupor and unconsciousne ss in children with iso­valeric ac idaemia.166,671 Moreover, an 8- to IO-foldrise of venous propionate and oct an oate (C8) isseen in pat ients with liver cirrhos is after duodenal

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939

or rectal instill ation without any influence on themental or neurological state.16X.691 It thereforeseems unlikely that the elevated level s of SCFA inpatients with hepatic encephalopathy are the pri ­mary cause of the neurological deterioration ,

A secondary role for SCFA, however, cann ot beexcluded as the coma-producing potential of sepa­rate toxic substances may be multiplied several­fold when they are pre sent together. In experi­mental anima ls the coma-producing effects ofammonia, fatty acid s (octanoate) and mercaptanshave been shown to be strikingly interdepen­dent.170,7!I In healthy animals, the dose of ammo­nium salt required to produce coma is sharply re­duced by the presence of a subcoma dose of eithera fatt y acid (octanoate) or mercaptan.Fv-" Iand theincidence of coma can be raised from zero to 100%by injection of subcoma doses of any of these sub­stances simultaneously. In rats with acute experi­mental hepatic co ma resulting from massive livernecrosis, the average blood level s of ammoni a, freefatty acids (oc tanoa te) and methanethi ol are muchlower than blood levels required to produce co main health y rats with each of these substances indi ­vidually. !" I When , however , health y rats are give na combination of doses of ammonia, octan oat e andmercaptan which produce blood level s in the rangeof those obse rved in rats with experiment al hepaticcoma, they becom e cornato se.P!'

4,3 Effect of Lactulose on Colonic SCFAProduction in Hepatic Encephalopathy

Although SCFA may not be the major ca use ofencephalopathy in patients with cirrhosis, the evi­dence of synergism in animalsl70.71 I sugges ts thatSCFA may playa role as an augmenter or intensi­fier of other putativ e neurotoxins, e.g. amm oni aand mercaptans. In incubated stool samples, fer­mentation of lactulose results in the form ation ofacetate prim aril y, whereas bacterial degradation ofblood, albumin and am ino acids significa ntly in­creases the production of all C2-6-SCFA, es pe­cially the potentially toxic C4-6-fatt y ac ids .119,431When lactul ose is added to incubations of aminoac ids, protein and blood, the SCFA produ ction is

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940

shifted almos t co mpletely toward s the nontox icC2-fatty acid, acetate. At lactul ose concen trationsof 10 to 25 mmol/L, corres ponding to a pH of ap­proximately 5, this effec t is largely mediated by theacidifying effect of lactulose.F'J pH-Independ entinhibition of blood and amino acid degradation toSCFA requires conce ntrations of lactulose exceed­ing 50 to 100 mmol/L.1431Th e co nce ntratio n oflactul ose after a sing le dose of 20g is 50 to 100mmol/L in the caecum.l''l with a co rres ponding de­crease in pH to values in the range of 3.5 to 6.1 inthe prox imal co lon.'6.231

In co ntras t, redu ction of faecal pH by 20 to 40gof lactul ose is small in magnitudelV' or eve n neg­ligiblel'" due to the rapid fermentation of lactul oseand the neutralisation ofluminal co ntents by bicar­bonate secretion. The result s obtained in vitro l431

indicate that lactul ose should be given in doses thatnot only acidify the caec um but also exceed thebuffer ing capac ity in the left co lon.

Enemas of lactul ose or glucose may be benefi­cia l supplemen ts to aid in obtaining this effect.

4,4 Possible Mec hanisms of Ac tion ofLactulose in the Treatment ofHepa tic Encephalopathy

Several mechani sms of action of lactulose in thetreatm ent of hepat ic ence pha lopathy apparentlyex ist (ta ble I). Th ey inc lude: (a) provision of areadi ly fermentable substrate, whic h enco uragesbacteri al proli feration and converts the norm al bal­ance betw een ammonia generation and utili sat ionfrom a net increase to a net decrease (assimil ation) ;(b ) a preferenti al use of lactulose as a carbon andenergy source, which exerts a sparing effect on thebacter ial metabol ism of both exogenous and en­dogenou s aminated co mpo unds with subsequentdecrease in the generation of ammonia; (c) an acid­ifyi ng effec t, which brings abo ut a general reduc­tio n in bacterial metabol ism, including that of am­moni a-p rodu cin g bact eria; (d) a laxative ac tion,which reduces the time for the production and ab­sor ption of ammonia and increases the so luble ni­trogen content of faeces ; and, (e) an ability to alterthe productio n of SCFA towards the non toxic ace-

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Ciali sen & Mortell sen

tate at the ex pense of the potent ially toxic C4-6­SCFA.

5. Conclusions

A single primary mech an ism of ac tio n oflactul ose in the treatment of co nsti patio n and he­pat ic ence phalopathy cannot be determined due toseveral possible effects the dru g may have. In pa­tient s with consti pation, the laxative effect of lac­tulose possibly res ults from the combination of: (a)flu id retenti on in the small intestine through theosmo tic act ivity of the unabsorbed disaccharide;and (b) interference with net flu id absorpti on in thecolon due to the osmotic effect of malabso rbed andintact sugars when the bacteri al fermentatio n ca­pacit y is exceeded. However, indivi dual sensi tivi­ties to the drug should be recogni sed, i.e. the ther­apeutic dose sho uld start at a relat ively low levelwi th a gradual increase according to the frequencyand consistency of the stoo ls.

Th e possibl e mec hanisms by whic h lactulosebenefits patient s with hepat ic encephalopathy in­cl ude: (a) increased faecal nitrogen excretion; (b)colonic acidification; (c) decreased tra nsit time;and (d) redu ced production of potentially toxicSCFA . In order to ob tain these effects it is recom­mend ed that the faeca l pH be measured in pat ientswith hepat ic ence phalopathy treated with lactu -

Table I. Possible mechanisms of action of lactulose in the treatmentof hepatic encephalopathy

Effect Result

Utilisation Stimulates bacterial growth and increasesincorporation of ammonia into bacterial protein(assimilation), and exerts a sparing effect on themetabolism of aminated compounds withsubsequent decrease in ammonia generation bycolonic bacteria

Acidifying Brings about a general reduction in bacterialmetabolism, including that of ammonia-producingbacteria

Laxative Reduces the colonic transit time. therebydecreasing the time available both for productionand absorption of ammonia and other potentiallytoxic substances

SCFA Enhances the production of the nontoxic acetatemodification at the expense of the potentially toxic C4-6-SCFA

Abbreviation: SCFA - short-chain fatty acids.

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Disaccharides and Colonic Flora

lose, and that the lactulo se dose should be titratedto pH levels <6 .0. Acidifying enemas, e.g. oflactulo se, lactitol or glucose, may be a beneficialsupplement in obtaining this effect.

ReferencesI. Cummings JH, Macfarlan e GT. The control and consequences

of bacterial fermentation in the human colon . J Appl Bacteriol199 1; 70: 443-59

2. Carulli N, Salv io lo GF, Manent i F. Ahsorpti on of lactulose inman. Digestion 1972; 6: 139-45

3. Saunders DR, Wiggins HS. Co nservation of mannitol , lactu­lose, and raffinose by the human co lon. Am J Physiol 1981;241 : G397 -402

4. Zarling EJ, Ruchim MA. Protein origin of the volatile fattyacids isobutyrate and isovalerate in human stool. J Lab ClinMed 1987; 109: 566- 70

5. Rasmussen HS, Holtug K, Morten sen PB. Degradat ion ofamino acids to short chain fatty acids in humans: an in vitrostudy. Scand J Gas troentero l 1988; 23: 178-82

6. Florent C, Flourie B, Leblond A, et al. Influence of chroniclactulo se ingestion on the colonic metabol ism of lactulo se inman (an in vivo study). J Cl in Invest 1985; 75: 608-13

7. Hove H, Morten sen PB. Colonic lactate metabolism and D-Iac­tate acidosis. Dig Dis Sci 1995; 40 : 320-30

8. Bustos D, Pons S, Pernas JC, et al. Fecal lactate and short bowelsyndrome. Dig Dis Sci 1994; 39: 23 15-9

9. Cu mmings JH, Pomare EW, Branch WJ, et al. Short chain fattyacids in human large intes tine, portal, hepatic and venousblood . Gut 1987; 28: 1221-7

10. Mortensen PB, Hove H, Clausen MR, et al. Fermentation toshort-chain fatty acids and lactate in human faecal batch cul­tures. lntra- and inter-individual var iation s versus variationscaused by changes in ferment ed saccharides. Scand J Gas­troenterol 199 1; 26: 1285-94

II. McNeil NI, Cummings JH, James WPT. Short chai n fatty acidabsorption by the human large intestine. Gut 1978; 19: 819-22

12. Ruppin H, Bar-Meir S, Soergel KH, et al. Absorption of short­chain fatty acids by the colon. Gastroenterol ogy 1980; 78:1500-7

13. Roediger WEW. Role of anaerobic bacteria in the metabolicwelfare of the coloni c mucosa in man. Gut 1980; 21: 793-8

14. Clausen MR, Mortensen PB. Kinetic studies on the metaboli smof short-chain fatty acids and gluco se by isolated rat co l­onocytes. Gastroenterolo gy 1994 ; 106: 423-32

15. Claus en MR, Morte nsen PB. Kinetic studies on colonocyte me­tabolism of short -chain fatty acids and glucose in ulcerat iveco litis. Gut 1995; 37: 684- 9

16. McNeil NI. The contribution of the large intestine to energysupplies in man. Am J Clin Nutr 1984 ; 39: 338-42

17. Vince A, Killingley M, Wrong OM. Effect of lactulose on am­monia production in a fecal incubat ion sys tem. Gastroenter­o logy 1978; 74: 544- 9

18. Mortensen PB, Holtug K, Rasmus sen HS. Short-chain fattyacid producti on from mono- and disaccharides in a fecal in­cubation system: implication s for colon ic fermentati on of di­e tary fiber in human s. J Nutr 1988; 118: 321-5

19. Mortensen PB, Rasmus sen HS, Holtug K. Lactulose detoxifi esin vitro short- chain fatty acid production in colonic contentsinduced by blood : implications for hepatic coma. Gastroen­terology 1988; 94: 750-4

<0 AdisInternati onal Limited . All rights reserved .

941

20. Peters SG, Poma re EW, Fisher CA. Portal and peripheral bloodshort chain fatty acid concentrations after caecal lactuloseinstillati on at surgery. Gut 1992; 33: 1249-52

21. Bond JH, Levitt MD. Use of pulmonary hydrog en measure­ments to quantitate carboh ydrate absorption: study of par­tially gas trectomized patient s. J Clin Invest 1972; 51:1219-25

22. Strocchi A, Cora zza G, Ellis CJ, et al. Detection of malabsorp­tion of low doses of carbohydra tes: accu racy of var ious brea thH2 criteria. Gastroenterology 1993; 105: 1404-10

23. Bown RL, Gibson JA, Siaden GE, et al. Effects of lactu lose andother laxatives on ileal and colonic pH as measured by aradiotelemetry device. Gut 1974; 15: 999- 1004

24. Bircher J, Muller J, Guggenheim P, et al. Treatment of chronicportal- system ic encephalopathy with lactulose. Lancet 1966;I: 890-3

25. Co nn HO, Leev y CM , Vlahcev ic ZR, et al. Co mparison oflactulose and neomycin in the treatment of chronic portal-sys ­temic encephalopathy: a doubl e blind controlled trial. Gastro­entero logy 1977; 72: 573-83

26. Holtug K, Clausen MR, Hove H, et al. The colon in carbohy­drate malabsorption: short-chain fatty acid s, pH, and osmoticdiarrhoea. Scand J Gastroenterol 1992; 27: 545-52

27. Conn HO, Floch MH. Effects of lactulose and lactobacil­lus acidophilus on the fecal flora. Am J Clin Nutr 1970; 23:1588-94

28. Vince A, Zeegen R, Drinkw ater JE, et al. The effect of lactuloseon the faecal nora of patients with hepatic encephalopathy. JMed Microbiol 1974; 7: 163-8

29. Riggio 0 , Varriale M, Testore GP, et al. Effect of lactitol andlactul ose administration on the fecal flora in cirrhotic pa­tients. J Clin Gastroe nterol 1990; 12: 433-6

30. Flourie B, Briet F, Florent C, et al. Can diarrhea induced bylactu lose be reduced by prolonged ingestion of lactulose'? AmJ Clin Nutr 1993; 58: 369-75

3 1. Stephen AM, Cu mmings JH. Mech anism of action of d ietaryfibre in the huma n colon. Nature 1980; 284: 283-4

32. Weber FL. The effect of lactulose on urea metabolism and ni­trogen excre tion in cirrhotic patie nts. Gastroe ntero logy 1979;77: 5 18-23

33. Mortensen PB. The effe ct of ora l-administered lactulose on co­lonic nitrogen metaboli sm and excre tion. Hepatolo gy 1992:16: 1350-6

34. Kot T V, Pett it-Young NA. Lactulose in the management ofcon­stipation : a cu rrent review. Ann Pharm acother 1992; 26:1277-82

35. Weijers HA, van de Kamer JH, Dicke WK, et al. Diarrhoeacau sed by deficiency of suga r splitting enzymes. ActaPaediatr 1961; 50: 55-71

36. Haemmerli UP, Kistler H, Ammann R, et al. Acquired milkintolerance in the adult caused by lactose malabsorption dueto a selective deficiency of intestinal lactase activity. Am .IMed 1965; 38: 7-30

37. Bustos Fernandez L, Gon zale z E, Marzi A, et al. Feca lacidorrhea. N Engl J Med 1971; 284: 295-8

38. Christopher NL, Bayless TM. Role of the small bowel and co­lon in lactose-induced diarrh ea . Gastroenterology 1971; 60:845-52

39. Hamm er HF, Santa Ana CA, Schill er LR, et " I. Studies of os­motic diarrhea induced in normal subjects by ingestion ofpolyethylene glycol and lactulose. J Clin Invest 1989; 84:1056-62

Drugs 1997 Jun: 53 (6)

942

40 . Argenzio RA, Moon HW, Kemeny LJ, et al. Colonic compen­sa tion in transmissible gastroenteritis of swine. Gastroenter­ology 1984; 86: 1501-9

4 J. Launiala K. The mechanism of diarrhoea in cong enital disac­charide malabsorption. Acta Paediat Scand 1968; 57: 425-32

42 . Perman JA , Modler S, Olson AC. Role of pH in production ofhydrogen from carbohydrates by colonic bacterial flora: stud­ies in vivo and in vitro. J Clin Invest 1981; 67: 643-50

43 . Mortensen PB, Holtug K, Bonnen H, et al. The degradation ofamino acid s, protein s, and blood to short-chain fatty acids incolon is prevented by lactulose. Gastroenterology 1990; 98 :353-60

44 . Phillips SF, Giller J. The contribution of the colon to electrolyteand water conservation in man . J Lab Clin Med 1973; 81:733-46

45 . Bond JH , Levitt MD. Quantitative measurement of lactose ab­sorption. Gastroenterology 1976; 70 : 1058-62

46. Debongnie JC, Phillips SF. Capacity of the human colon toabsorb fluid . Gastroenterology 1978; 74: 698-703

47 . Chauve A, Devroede G, Bastin E. Intraluminal pressures duringperfusion of the human colon in situ. Gastroenterology 1976;70 : 336-40

48 . Zieve L. The mechanism of hepatic coma. Hepatology 1981; I:360-5

49 . Vince A, Down PF, Murison J, et al. Generation of ammoniafrom non-urea sources in a faecal incubation system. Clin SciMol Med 1976; 51 : 313-22

50 . Haemmerli UP, Bircher J . Wrong idea , good results. (Thelactulose story .) N Engl J Med 1969; 281 : 441-2

51 . Zeegen R, Drinkwater JE, Fenton JCB , et al. Some observationson the effects of treatment with lactu lose on patients withchronic hepat ic encephalopathy. Q J Med 1970; 39: 245-63

52. Agostini L, Down PF, Murison J, et al. Faecal ammonia and pHduring lactulose admin istration in man : comparison withother cathartics. Gut 1972; 13: 859-66

53 . Weber FL, Banwell JG , Fresard KM, et al. Nitrogen in fecalbacterial, fiber, and soluble fractions of patients with cirrho­sis : effects of lactulose and lactulose plus neomyci n. J LabClin Med 1987; 110: 259-63

54 . Samson FE, Dahl N, Dahl DR. A study on the narcotic actionof the short chain fatty acids. J Clin Inves t 1956; 35 : 1291-8

55. White RP, Samson FE. Effects of fatty acid anions on the elec­troencephalogram of unanesthetized rabbits. Am J Physiol1956; 186: 271-4

56. Oldendorf WH oCarrier-mediated blood-brain barrier transportof short-chain monocarboxylic organic acids . Am J Physiol1973; 224: 1450-3

57 . Linscheer WG, Blum AL, Platt RR. Transfer of medium chainfatty acids from blood to spinal flu id in patients with cirrhosis.Gastroenterology 1970; 58 : 509- J5

© Adi s International Limited . All right s reserved.

Clausell & Mortellsell

58. Dahl DR. Short chain fatty acid inhibition of rat brain Na-Kadenosine triphosphatase. J Neurochem 1968; 15: 815 -20

59 . Trauner DA. Regional cerebral Na+K+ ATPase activity follow­ing octanoate administration. Pediatr Res 1980; 14: 844-5

60 . Muto Y, Takahashi Y. Gas chromatographic determination ofplasma short chain fatty acids in diseases of the liver. J JpnSoc Int Med 1964; 53 : 828-39. Cited in Postgrad Med 1965;37: A 158

61. Lai JCK , Silk DBA , Williams R. Plasma short-chain fatty ac idsin fulminant hepatic failure . Clin Ch im Acta 1977; 78: 305- 10

62 . Clausen MR, Mortensen PB, Bendt sen F. Serum levels of short­chain fatty ac ids in cirrhosis and hepat ic com a. Hepatology1991; 14: W40-5

63. Hommes FA, Kuipers JRG , ElemaJD, et al. Propionicacidemia,a new inborn error of metabolism . Pediatr Res 1968; 2: 519-24

64 . Bran ski D, Gale R, Gross-Kieselstein E, et al. Propion ic acide­mia and anorectal anomalies in three siblin gs . Am J Dis Child1977; 131: 1379-81

65 . Hillman RE. Simple, rapid method for determination of propi­onic acid and other short-chain fatty acids in se rum. ClinChern 1978; 24 : 800-3

66. Budd MA, Tanaka K, Holmes LB, et al. Isovaleric ac ide mia:clinical features of a new genetic defect of leucine metabo­lism . N Engl J Med 1967; 277 : 321-7

67. Duran M, Sprang FJ van, Drewes JG , et al. Two sisters withisovaleric acidaemia, multiple attacks of ketoac idosis andnormal development. Eur J Pediatr 1979; 131: 205-11

68. Scheppach W, Richter F, Joeres R, et al. Systemic avail abilityof propionate and acetate in liver cirrhosis. Am J Gas­troenterol 1988; 83 : 850-3

69. Linscheer W, Castell DO, Platt RR. A new method for evalua­tion of portosystemic shunting. Gastroenterology 1969; 57:415-23

70. Zieve FJ, Zie ve L, Doi zaki WM, et al. Synergism between am­mon ia and fatty acids in the production of coma: implicationsfor hepatic coma. J Pharmacol Exp Ther 1974; 191: 10-6

71. Zieve L, Doizaki WM , Zieve FJ. Synergism between rnercap­tans and ammonia or fatty acids in the production of com a: apossible role for mercaptans in the pathogenesis of hepaticcoma. J Lab Clin Med 1974; 83: 16-28

Correspondence and reprints: Dr MetteRyeClausell, Depart­ment of Medicine CA 2101, Division of Gastro enterology,Rigshospitalet, Blegdamsvej 9, DK-2100 Cop enhagen 0,Denmark.

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