Comparative Modes of Action of Lactitol and Lactulose in the Treatment of Hepatic Encephalopathy

Gut: first published as 10.1136/gut.28.3.255 on 1 March 1987. Downloaded from

Guit, 1987, 28, 255-259

Comparative modes of action of lactitol and lactulose in the treatment of hepatic encephalopathy

D H PATIL, D WESTABY, Y R MAHIDA, K R PALMER, R REES, M L CLARK, A M DAWSON, AND D B A SILK From the Department of Gastroenterology and Nutrition, Central Middlesex Hospital, London, and Department of Gastroenterology, St Bartholomew's Hospital, London

SUMMARY Lactitol, an unabsorbed sugar with defined laxative threshold and superior taste properties has been suggested as an alternative to lactulose in the treatment of hepatic encephalopathy. In the present study we have compared the colonic metabolism of the two sugars using an in vitro faecal incubation system. Both sugars were readily metabolised by faecal bacteria producing volatile fatty acids and the metabolism was inhibited by neomycin. The effect of lactitol and lactulose on terminal ileal and colonic pH was monitored in six normal subjects using a radiotelemetry technique. Both sugars significantly lowered right colonic pH (basal -6 51±0.48 vs lactitol -563±0 50; lactulose -5*18±0*82, p<0.05). The pH of rest of the colon and terminal ileum was unaffected. Neomycin given concurrently with lactulose abolished acidification of right colon. As lactitol and lactulose have similar effects within the colon, lactitol would appear to have a role in the treatment of hepatic encephalopathy. As neomycin antagonises the effect of lactulose in the colon, its concurrent use may be less effective in the treatment of hepatic encephalopathy. http://gut.bmj.com/

Lactulose, an unabsorbed disaccharide (1:4, B- effects of lactulose and lactitol on ileal and colonic galactosido-fructose) has been extensively used pH in vivo were compared using a radiotelemetry in the treatment of hepatic encephalopathy.`' device in normal human subjects.

Lactulose, however, is excessively sweet and conse- The combination of neomycin and lactulose is still on September 24, 2021 by guest. Protected copyright. quently is unacceptable to some patients. Lactitol (B- used in the treatment of hepatic encephalopathy galactosido-sorbitol), a disaccharide analogue of despite the theoretical possibility that neomycin may lactulose has recently been described. This sugar is inhibit the bacterial metabolism of lactulose. We highly water soluble, less sweet than lactulose and is have therefore taken the opportunity of investigating not absorbed in the human small intestine.4 It has the effect of neomycin on colonic lactulose meta- seemed to us therefore that lactitol might have a bolism in vitro and in vivo. potential as an alternative therapeutic agent to lactulose in the treatment of hepatic encephalopathy. Methods A recent open clinical tria15 supports this suggestion as lactitol appeared to be as effective as lactulose in COLONIC BACTERIAI METABOLISM OF LACTITOL the management of patients with this condition. IN VITRO In the present study experiments were designed to An in vitro culture system was developed to simulate characterise the colonic metabolism of lactitol. In as closely as possible the anaerobic metabolism of the first, an in vitro faecal incubation system was human colonic bacterial flora in vivo. A glass developed to simulate anaerobic fermentation of reservoir painted black externally to exclude light lactitol by human faecal bacteria. In the second, the was used as the reaction chamber. Normal human volunteers passed approximately 25 g faeces into a Address tor correspodicrc: Dr DL H Patil, [)cpt of' Gistrocntcrology & beaker containing degassed water. The stool was Nutrition (Central Middlcscx Hlospiti.t I ondon NWI() 7NS. immediately mixed with 500 ml nutrient medium in Reccived for publication 3 July 1986. the reaction chamber which contained, NaCl 68 255 Gut: first published as 10.1136/gut.28.3.255 on 1 March 1987. Downloaded from

1-56 Patil, WeslabY, Mahida, Palwtier, Rees, Clark, Dawsot., atnd Silk mmol/l; KCI 5 mmol/l, a free L-amino acid mixture acid and samples quantified from peak height (0.47 mg amino acid nitrogen/l, Vamin N Kabivitrum measurement. Ltd), sodium taurocholate 10 mmol/l to inhibit growth Lactic acid was measured as previously described` of non-colonic bacteria and either lactitol or lactulose with a standard lactate dehydrogenase kit 20 g/l. The reaction mixture was stirred continuously (Boehringer Mannheim Ltd, London). and maintained at 37"C. The surface of the mixture was continuously flushed with 02 free N2 to maintain EFFECT OF lIACTUl.OSE ANI) I ACTITOI ON anaerobicity. The colonic mucosa in vivo normally TERMINAI ILEAI AND COL ONIC pH secretes HCO3 ions" whereby the intraluminal pH of Six healthy volunteers all members of the department colon is maintained in the range of 6-7.7 In the gave their informed consent and participated in a present system the pH of reaction mixture was randomised crossover study. The study was approved maintained at 7.0 by continuous titration of l M/l by the Ethical Committee of Brent Area Health NaOH using an autoburette (Radiometer, Copen- Authority. pH sensitive radiotelemetry capsules hagen, Denmark). (Remote Control Systems Ltd, London) were cali- In pilot studies, aliquots of freshly passed faeces brated in standard buffer solutions at 37°C and then and reaction mixture were cultured after 24 hour swallowed. The capsules were allowed to pass incubation. Cultures from the reaction mixtures through the intestine and pH recordings were showed the presence of both aerobic and anaerobic obtained for five to 10 minute periods every one to organisms representative of those cultured from two hours. The full details of the technique used to aliquots obtained from the same faecal samples measure intraluminal pH by radiotelemetry have before incubation. been described previously.' Initially the site of Aliquots of samples (20 ml) were collected from capsule was determined by occasional radiographic the reaction chamber at 0 and 24 h incubation into a screening. In later studies we found that the capsule universal container maintained at 4°C, which was could be satisfactorily localised by identifying the site then immediately frozen and stored at -20°C until of maximum signal strength and then following the analysis of volatile fatty acids was carried out. pH changes along its course. The capsule remained in the caecum for six to 24 hours and the passage of EXPERIMENTAL DESIGN capsule from terminal ileum into caecum was Stool samples from five normal human subjects were characterised by a sudden and sustained fall in pH http://gut.bmj.com/ incubated with the lactitol containing medium, and which enabled us to identify its entry from terminal separate stool samples from the same subjects incu- ileum into the caecum. Mean values of repeated bated with lactulose containing medium. In three measurements of pH from terminal ileum, right further experiments, stool samples were incubated colon, left colon and rectum were obtained. The with the lactulose containing medium and after rectum was identified by noting maximum signal establishing that bacterial fermentation was proceed- strength on the lower sacrum or by recording the pH ing, as evidenced by titration requirements of NaOH just before the capsule was passed. In only one study on September 24, 2021 by guest. Protected copyright. to maintain pH at 7.0, neomycin was added in doses which was abandoned the pH capsule remained in the of 100, 300, and 500 mg respectively and incubation right colon for more than 36 hours. In all other carried out for 24 hours as described above. studies it was possible to obtain the pH measurements in the terminal ileum, right colon, left colon, ANALYTICAL TECHNIQUE and rectum. In majority of cases the pH of freshly The volatile fatty acid levels in the culture medium passed stool was also measured. were measured by a modified gas liquid chromato- graphy method as previously described.' The EXPERIMENTAL I)ESIGN chromatograph used was a Pye Unicam 104 with a The subjects were randomly assigned to receive a flame ionisation detector. Samples of the culture normal diet, or this supplemented with lactulose and medium (1 ml) were mixed with 0-1 ml of concen- lactitol. Both sugars were consumed for three to four trated HCI and 0.2 ml 50 mmol/l 3-methyl valeric acid days in increasing doses so as to produce two to (internal standard). The mixture was centrifuged and three semiformed motions/24 h. The final doses of the supernatant (2 ul) injected into a column of 5% lactulose and lactitol administered were 30-80 g/24 h poly neopentyl glycol sebacate, 1% phosphoric acid and 40-180 g/24 h in two to four divided daily doses. and Anakrom A (80-100 mesh) packed in a 1.8x All subjects undertook normal daily activities and 0(002 m glass column (Field Instruments Co Ltd, each study period was separated by at least seven Weybridge, Surrey) maintained at 1 10C. days to allow normalisation of colonic bacterial flora Standard curves were constructed by injecting and bowel habit. calibrated amounts of a mixture of each volatile fatty In three of the subjects, the lactulose study was Gut: first published as 10.1136/gut.28.3.255 on 1 March 1987. Downloaded from

C'omuparative mIodes of a(ctioni of l(Ictitol((1(1 la( tlilose itn the treatment of hepatic emlcepell(llopati '2 257 repeated as described except that neomycin at a dose considerably superior to its analogue lactulose. of 0.5 to 1.0 g three to four times a day was also Recent intestinal perfusion experiments have shown administered. that lactitol is neither hydrolysed nor absorbed intact by the human small intestine.' Further studies have STATISTICAI. ANALYSIS shown that a substantial proportion of orally ingested The statistical differences of intraluminal p1H changes lactitol is metabolised inl i'it'o and the estimated were assessed using the paired t test. caloric value of this sugar has been found to be approximately 2-3 kcal/g (Grimble et al, unpublished Results data). The disparity between the results of small intestinal perfusion experiments and the in vivo

I COt.ONIC BACTERIAI. METABOI.ISM OF caloric utilisation studies suggested that the colon

IACTITOL ANI) I ACTUILOSE IN VITRO was the major site of lactitol metabolism. As lactitol The titration requirement of NaOH to maintain pH also acts as an osmotic cathartic agent,4 we wondered 7-0 during lactitol incubation was 103+33 mmol/24 h whether this sugar might have a place in the treat- (mean+SD; n=5) and 152+22 mmol/24 h during ment of hepatic encephalopathy. The results of the in lactulose incubation. The volatile fatty acids identi- vitro culture experiments clearly show that human fied during both incubation studies were acetic acid, faecal bacteria, under anaerobic conditions utilise propionic acid, butyric acid, and lactic acid. The lactitol as an energy substrate and that it was the concentrations of volatile fatty acids liberated during release of volatile fatty acids that lowered the pH of the 24 hour incubation period are summarised in the reaction mixture. Lactitol was metabolised in a Table 1. similar manner to lactulose with acetic acid being the When neomycin at doses of 100 and 30)0 mg was predominant volatile fatty acid produced in both added to lactulose containing medium, the titration cases. There are no published studies to compare our requirements were 140 and 130 mmol NaOH/24 h. At data of in vitro lactitol metabolism by colonic a dose of 5t)( mg however, lactulose metabolism bacteria. A previous study of lactulose metabolism appeared almost completely inhibited for 24 hours by colonic bacteria, however, suggested that lactic and the reaction had a titration requirement of only acid was the predominant metabolite produced." 10 mmol NaOH/24 h. This study, however, was carried out using pure cultures of different species of faecal bacteria and not http://gut.bmj.com/ 2 EFFFCT OF IACTITOI ANI) IACTUIOSE ON the mixtures of species that are found in the faeces. TERMINAI IIEAL ANI) COIONIC pH The similarity of handling of lactulose and lactitol In the control experiments there was a significant fall by human faecal organisms in our in vitro culture in pH between the terminal ileum (7.51+t)37) and system prompted us to compare the effects of the two right colon (6.51+0.48; p<0.01). The pH values sugars on the luminal pH of the terminal ileum, found in the right colon, left colon and rectum were colon, rectum as well as faecal pH in vivo. The pH similar to those previously described7 and are shown profiles of the terminal ileum, and colon were found on September 24, 2021 by guest. Protected copyright. in Table 2. to be very similar to those reported by Bown et al who There was a significant fall in right colonic pH used the same experimental technique.' We have during ingestion of lactitol to 5.63+0(54 (p<0 (5) confirmed that lactulose when ingested in sufficient and lactulose to 5.18+0(82 (p<0).01). The values doses to produce two to four semi-formed motions a obtained during the ingestion of the two sugars were, day lowers the pH of the right colon and no significant however, not significantly different. Neither sugar changes being noted in pH in the other regions of the had a significant effect on the luminal pH of the colon, terminal ileum or faeces. The present findings terminal ileum, left colon or the faeces. show that lactitol has an exactly similar effect to that When lactulose was administered with neomycin, of lactulose on colonic pH. the pH profile of the terminal ileum, right colon, left colon, rectum and faeces as shown in Table 2 were faa not significantly different from those recorded during Table 1 Concentratiotn of'volatileJt ac.id].s (mtmolll) the control experiments. produiced ulfter24 lIfiaecal incubatotio Discussion Ltctitol LaciOlot.,e Acctic acid 40±13 74+22 Propionicazcid 13±4 15±6 Lactitol is produced by hydrogenation of lactose and Butyric acid 23± 16 2±1 should soon be available as a pure, crystalline powder Lactic acid 1 ± 1 2+1 which is highly soluble in water. With a sweetness of 350O compared with sucrose, its taste properties are (Mcan±SD n =5). Gut: first published as 10.1136/gut.28.3.255 on 1 March 1987. Downloaded from

258 Patil, Westaby, Mahida, Palmer, Rees, Clark, Dawson, and Silk

Table 2 Effect oflactulose and lactitol on pH ofterminal ileum, colon andfaeces

t1 TJerinital ileum Riglit colon Left colont Rectumn kaeces Basal 6 7-51 ±0-37 6 51+0.48* 6-33±0+72 6-53±0-69 6-07±0-31 Lactulosc 6 7-23±0+44 5-18±0I82t 5-67±1-03 5-93±31-40 5-72± 167 Lactitol 6 7-08±0(41 5-63±0-54T 6-12±0-63 6-58±0-40 6-54±0+46 Lactulosc+ncomycin 3 7.3 ±0-41 6-4 ±0+96 6-4 ±0-6 6-2 ±0-4

*Tcrminal ilcum vs right colon p<)-()(I; tBasal vs lactulosc p<0(-1; tBasal vs lactitol p<0.05. Values arc mcan ±SD.

There are a number of explanations as to why the pathy on the basis presumably that the combination change in luminal pH induced by the two sugars of the two is superior to using either drug alone. occurs only in the right side of the colon. Firstly the Although there are several studies showing that luminal concentration of unabsorbed sugars will be lactulose and neomycin when used on their own high in the proximal colon. Therefore it is likely to be are equally effective in the treatment of hepatic the major site of bacterial fermentation, producing encephalopathy,9'-225 there are no controlled clinical maximum concentration of volatile fatty acids and trials showing that combination therapy is superior to consequently lowering the pH. Secondly, the volatile the use of either drug on its own.' During the course fatty acids are avidly absorbed from the colonic of the present study we took the opportunity of mucosa,''23 so that their effect on luminal pH will examining the effect of neomycin on the colonic diminish as luminal contents move distally. Finally it metabolism of lactulose both in vitro and in vivo. The is known that bicarbonate ions are secreted into the findings show that neomycin inhibits the bacterial lumen of the colon against both chemical and metabolism of lactulose in vitro and negates the effect electrical gradients" 4 which will neutralise the acid. of lactulose on right sided colonic pH. Our findings The exact mechanisms whereby lactulose exerts its therefore not only question the validity of combina- beneficial effect on hepatic encephalopathy are not tion therapy in hepatic encephalopathy, but raise the fully understood. Available evidence suggests that distinct possibility that neomycin might actually lactulose acts by influencing the ammonia meta- inhibit the beneficial effect of lactulose in this http://gut.bmj.com/ bolism in the intestine. "" Ammonia is absorbed by condition. non-ionic diffusion'" and it has been suggested that ammonia absorption is reduced as a consequence of We thank Dr F Ahmad and Dr D A McSwiggan for conversion of ammonia to the ionised form in acid culturing the samples; Dr G K Grimble and Mr M media.'" Such an explanation appears to be sup- West for measuring the volatile fatty acids. ported by studies that have measured ammonia concentrations in portal vein radicals during acidifi- References cation of colon.'7 Studies on ammonia loss in the I Conn HO, Lieberthal MM. The hepatic coma syndromes on September 24, 2021 by guest. Protected copyright. faeces, however, have not shown the expected and lactulose. Baltimore: Williams and Wilkins, 1979. increase."'' Vince et al'6 claim that net ammonia 2 Elkington SG. Lactulose. Gut 1970; 11: 1043-8. production is decreased after ingestion of unab- 3 Van Velthuijsen JA. Food additives derived from sorbed sugar, firstly by facilitating growth of anaero- lactose; lactitol and lactitol palmitate. J Agric Food bic bacteria and incorporating ammonia into Chem 1979; 27: 680-6. bacterial proteins and secondly lowering the pH will 4 Patil DH, Grimble GK, Silk DBA. Intestinal absorption inhibit the growth of proteolytic and laxative threshold of lactitol - a new hydrogenated organisms.7' Finally derivative of lactose. [Abstract]. Gut 1985; 26: Al 114. it has been suggested that the cathartic effect of 5 Lanthier PL, Morgan MY. Lactitol in the treatment of lactulose may serve to both reduced ammonia pro- chronic hepatic encephalopathy: an open comparison duction and absorption. Whatever may be the with lactulose. Gut 1985; 26: 415-20. mechanism whereby lactulose exerts its beneficial 6 Giller J, Phillips SF. Electrolyte absorption and effect on hepatic encephalopathy, the present in vitro secretion in human colon. Am J Dig Dis 1972; 17: and in vivo studies show that lactitol is handled in the 1003-11. colon in a strikingly similar fashion to lactulose. 7 Bown RL, Gibson JA, Sladen GE, Hicks B, Dawson Lactitol has superior taste properties and it is toler- AM. Effects of lactulose and other laxatives on ileal and ated better colonic pH as measured by radiotelemetry device. Gut by patients.' We would therefore suggest 1974; 15: 999-1004. that this sugar has potential as an alternative to 8 Roediger WEW, Moore A. Effect of short chain fatty lactulose in the treatment of hepatic encephalopathy. acid on sodium absorption in isolated human colon The combination of lactulose and neomycin is perfused through the vascular bed. Dig Dis Sci 1981; 26: often used in the treatment of hepatic encephalo- 100-6. Gut: first published as 10.1136/gut.28.3.255 on 1 March 1987. Downloaded from

Comnparative n1io(les ofaction of'lactitol a11( lactiulose in the treatment ofhepatic encephalopathy 259

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