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Lactitol vs. lactulose in the treatment of chronic recurrent portal-systemic encephalopathy
106
Journal of Hepatology, 1988; 7: 106-110
Elsevier HEP 00424
Lactitol vs. lactulose in the treatment of chronic recurrent portal-systemic encephalopathy
D. H e r e d i a , J. T e r 6 s , N. O r t e u a n d J. R o d 6 s Liver Unit and Neurology Service, Hospital Clinic i Provincial. Medical School, Barcelona (Spain)
(Received 12January 1988) (Accepted 22 February 1988)
Summary To compare the efficacy and patient acceptability of lactitol vs. lactulose in chronic recurrent portal-systemic encephalopathy (PSE), 25 cirrhotic patients with a history of repeated episodes of hepatic encephalopathy who required chronic administration of lactulose were included in a controlled cross-over cli0ical trial in which patients received, at random, lactitol (at an initial dosage of 10 g/6 h) or lactulose (15 ml/6 h, 66% w/v, containing 10 g of lactulose) during a 3 month period and then crossed-over to the alternative treatment for the following 3 months. Doses were adjusted to obtain two bowel movements per day. During the study period the daily protein intake was 40-60 g. Clinical and analytical data (including ammonia levels) were obtained, an E E G and the number connection test were performed and the PSE index was determined before treatment and monthly until the end of the treatment. No significant differences were found between the effects of lactitol and lactulose on the neurological and biological parameters, suggesting that the two treatments could be considered as equally effective. Lactitol was significantly better tolerated than lactulose (P = 0.02), the taste of which was assessed as being too sweet and provoking nausea. In conclusion, lactitol is a good alternative to lactulose for patients with chronic recurrent PSE, especially in those who do not tolerate the excessive sweetness of lactulose.
Introduction Lactulose (fl-galactoside-fructose) is a synthetic disaccharide that is not absorbed in the small bowel and produces a cathartic effect and a decrease in intraluminal pH when it reaches the right [1,2] colon. Lactulose has been the treatment of choice of portalsystemic encephalopathy (PSE) [3] since it was intro-
duced in 1966 [4]. This substance has, however, some disadvantages, mainly its contamination with other sugars such as galactose and fructose, which theoretically may impair glucose metabolism in cirrhosis [5]. This effect is, however, irrelevant, since in commercial preparations of lactulose syrup the maximum contamination with monosaccharides is less than 15%, each 15 ml dose of syrup thus usually contain-
Correspondence: Dr. J. Ter6s, Servicio de Hepatologia, Hospital Clinic i Provincial, Villarroel, 170, 08036 Barcelona, Spain.
0168-8278/88/$03.50 (~) 1988 Elsevier Science Publishers B.V. (Biomedical Division)
LACTITOL VS. LACTULOSE IN PSE
107
ing about 2 g of monosaccharides. A n o t h e r disadvantage of lactulose is its excessively sweet taste that may provoke aversion and nausea in some patients, especially in those with chronic recurrent PSE who need long-term therapy with this compound. In some European countries lactulose is also available as a chemically pure white crystalline powder which is less sweet than the syrup. Recent investigations [6-9] suggest that lactitol, a soluble disaccharide (fl-galactoside-sorbitol) with effects similar to those of lactulose, may be useful in the treatment of PSE in cirrhotics. Lactitol is supplied as a chemically pure white crystalline powder with a mildly sweet taste. The aim of the present study was to compare the efficacy of and tolerance to lactitol and lactulose in cirrhotic patients needing long-term treatment.
Patients and Methods
Twenty-five cirrhotic patients with chronic or recurrent PSE requiring long-term therapy with lactulose were included in the study. Cirrhosis was documented in all cases by means of needle or surgical biopsy. Fifteen patients were alcoholics, whereas in the remaining cases the etiology of cirrhosis was considered posthepatitic in six and cryptogenic in four. TABLE 1 BIOCHEMICAL DATA OF PATIENTS AT ENTRY INTO THE STUDY
Hemoglobin (g/dl) Platelets (103/ml) Quick (%) NH4 (/tmol/100 ml) Total protein (g/I) Albumin (g/I) Glucose (mg/dl) Alkaline phosphatase (U/I)~ Bilirubin (mg/dl) Aspartate aminotransferase (U/I)b y-Glutamyltransferase (U/I)¢
Mean S.D.
Minimum Maximum
12 2.12 115 51 65.7 17.34 154.3 41.2 72.8 8.1 32.9 4.4 107.3 51.8
9.10 53 45 86.7 58 26 72
15.70 250 100 225.3 88 42 292
342.5 261.8 2.8 3.9
70 0.8
984 17.3
10
280
9
646
85.3
70.2
126.4 201
Normal values: a280 U/l; b40 U/l; c40 U/I.
All patients had had a portal-systemic shunt because of variceal bleeding between 1 and 7 years before their inclusion in the study, and all had clinical evidence of repeated episodes of PSE and had been treated with iactulose during a period of at least 3 months before the study. Patients with advanced hepato-renal syndrome or liver cell carcinoma were not included in the study. After giving their informed consent, patients were randomly allocated, following a random number table, to treatment with either lactulose or lactitol, without a washout period. Patients were put on a standard diet with a protein content of 40-60 g, and no other treatment for PSE was allowed during the study. Lactulose was administered as a syrup at an initial dosage of 15 ml (66% w/v; 15 ml of syrup contains 10 g of lactulose) every 6 h, and lactitol as a powder at a dosage of 10 g every 6 h. Dosages of both compounds were adjusted with the aim of procuring two soft bowel movements per day. After 3 months, patients were crossed-over to the alternative treatment for a second 3 month period, without a washout period. Before the beginning of the treatment and every month during the 6 months' duration of the study, patients were visited by the same physician (D.H.) in the outpatients department and underwent a physical and neurological examination, electroencephalogram ( E E G ) and a battery of biochemical tests (Table 1). PSE sum and PSE index were calculated according to Conn et al. [10]. Qualitative variables were evaluated in a semiquantitative way according to the following scale: 0 = normal, 1 = mildly abnormal, 2 = markedly abnormal, 3 = severely abnormal. During the whole period of treatment, patients filled in a questionnaire with daily dosage, stool frequency and consistency, acceptability of the compound (graded as 1 = very poor, 2 = poor, 3 = mild, 4 = very good), side effects and other phenomena, if any. The comparison of efficacy of lactitol and iactulose was made by paired tests, Student for normally distributed variables and Wilcoxon for ordinal variables, for the results obtained at month 3 and month 6 after a 3 month period of treatment with lactitol or lactulose. This study was approved by the Ethics and
108
D. HEREDIA et al.
TABLE 2
TABLE 3
QUANTIFIED NEUROLOGICAL STATE AT ENTRY INTO THE STUDY, AFTER 3 MONTHS OF LACTITOL AND AFTER 3 MONTHS OF LACTULOSE
TOLERANCE TO LACTITOL AND LACTULOSE
At entrya Flapping Consciousness Memory Intellect Speech Handwriting Sum PSE PSEindex
0.95 + 0.82 0.45 + 0.60 1.05 + 0.68 0.55 + 0.60 1.5 + 0.57 1.15 + 1.03 7.25+3.3 25.9+ 11.8
After lactitol
After lactulose
Side effect
a All patients on entry were under lactulose therapy when they underwent neurological examination. Research C o m m i t t e e of the Hospital Clinic i Provincial.
Results
Five of the 25 patients had to be excluded from the trial. One of them died after the first visit from pneumonia and sepsis and a n o t h e r after the second visit from gastrointestinal bleeding. The remaining three patients d r o p p e d out during the follow-up, one after the first visit and two after the second visit. F o u r t e e n of the 20 patients analyzed were male and six female. Mean age was 54.5 + 2.1 years and the mean duration of the disease at the beginning of the treatment was 2.5 + 2 years. All patients with alcoholic cirrhosis claimed to have s t o p p e d drinking after the portal-systemic shunt. Two-thirds of the patients had flapping t r e m o r when they e n t e r e d the study and seven had ascites. Quantified neurological state before the start of the study is shown in the first column of Table 2 and the results of biochemical tests in Table 1. The mean daily dosages required to obtain two bowel m o v e m e n t s per day were 60 --- 29.4 ml of lactulose syrup (containing 40.2 + 19.6 g of lactulose) and 35.6 + 17.5 g of lactitol. No statistically significant differences were found in the assessment of the neurological state, as shown in Table 1, or in the biological data between the two therapeutic periods (lactulose or lactitol). Venous
Lactulose
cases mentions cases mentions
P
1.15 + 0.87 1 + 0.56 0.42 0.65 + 0.58 0.4 + 0.5 0.76 1.4 + 0.59 1.15 + 0.67 0.55 0.7 + 0.73 0.75 + 0.55 0.75 1.45 + 0.68 1.5 + 0.68 0.52 1.05 + 0.88 1.1 + 0.78 0.44 7.19+2.8 8.12+5.3 0.49 25.7+9.9 29+ 19.1 0.49
Lactitol
Meteorism Nausea Abdominal discomfort Too-sweet taste Dyspepsia Gastric acidity Diarrhea
6 0 3 0 0 I 2
11 6 1 2
2 4 2 7 1 0 2
2 5 2 12 1 2
blood a m m o n i a level was 152.09 + 31.57 ~mol/100 ml after lactulose and 140.66 + 44.87~mol/100 ml after lactitol (t = 1.20, n.s.). B l o o d glucose levels did not change significantly either after lactulose (before: 107.4 + 44.6 mg/dl, after: 114 ___67.9 mg/dl, t = 0.78, n.s.) or after lactitol (before: 99.2 + 24.8 mg/dl, after: 114.(~ + 62.3 mg/dl, t = - 1 . 3 4 , n.s.). With regard to the data r e c o r d e d by the patient, there were no differences between the two treatments in stool frequency (1.65 + 0.6 for lactitol and 1.57 + 0.63 for lactulose) and consistency. M o r e than half the patients achieved the two desired soft motions a day with the two sugars. The remaining patients had only one motion a day, but soft and copious. Acceptability was b e t t e r for lactitol than for lactulose (Wilcoxon test, z = -2.1917, P = 0.02), the taste of which was assessed as being too sweet and provoking nausea. M e t e o r i s m and a b d o m i n a l discomfort were slightly m o r e frequent with lactitol than with lactulose (Table 3). No adverse reactions leading to withdrawal were observed with either of the treatments.
Discussion
PSE is a frequent complication of cirrhosis of the liver, especially in patients who have large spontaneous or surgical portal-systemic shunts [11]. Although diverse metabolic disorders have been recently implicated in the pathogenesis of PSE [12-15], the classic hypothesis of the passage to the general circulation of toxic nitrogenous substances, mainly
LACTITOL VS. LACTULOSE IN PSE ammonia, formed in the intestine by bacterial action on proteins remains widely accepted. Favoring this hypothesis, the most effective treatment of PSE is directed towards reducing the intestinal production and absorption of these toxic substances [5]. Lactulose was introduced in the therapy of PSE in 1966 by Bircher et al. [4] and it is, at present, the treatment of choice for this complication. The mechanism by which this substance improves PSE is uncertain. Lactulose is a synthetic disaccharide, derived from lactose, which is not absorbed in the bowel due to the lack of an appropriate disaccharidase in the human intestinal mucosa. Therefore, it is unchanged upon reaching the lower bowel where it is broken down by bacteria producing volatile fatty acids (acetic, propionic, butyric and lactic) [2]. Classically it has been suggested that lactulose improves PSE due to its laxative properties, and also because the reduction of the intraluminal pH induced by the bacterial transformation of lactulose would favor the conversion of ammonia imo ammonium, which is almost incapable of passing through the intestinal wall [16]. A complementary hypothesis is that lactulose may provide a carbohydrate source to facilitate ammonia utilization by gut bacteria [17]. In 1982, Bircher et al. [6] successfully treated a patient with a portacaval shunt and chronic PSE with lactitol. Lactitol is also a synthetic disaccharide (/3galactoside-sorbitol) that is synthesized almost pure in chrystalline form and is soluble in water at 25 °C. It can be supplied as a powder or tablets and its taste is less sweet than that of lactulose. The mechanism by which lactitol improves PSE is probably similar to that of lactulose, since it is not absorbed by the small intestine and is broken down by colonic bacteria [2,18]. Since the first experience of Bircher et al. [6], lactitol has been compared with lactulose in three published investigations. One of them [7] was an open comparison in five patients suffering from chronic PSE that had been treated for 3 month periods with lactulose and lactitol. This study showed that lactitol was at least as efficacious as lactulose 'but was more acceptable because its cathartic effect was more predictable, its formulation was more convenient and its
109 less sweet taste preferred'. Recently, Morgan et al. [8] published the results of a randomized, cross-over comparison between lactitol and lactulose in which both sugars were administered as a solution, identical in taste and appearance and with similar physicochemical properties. Twelve patients requiring longterm treatment for PSE were treated for periods of 3 months with each sugar in a double-blind form. From this study the authors concluded that the treatments were equally effective in the treatment of chronic PSE and that the incidences of side effects were not statistically different. Finally, we compared lactulose and lactitol in a series of 40 cirrhotic patients with an acute episode of PSE who were randomly treated with one of the two sugars [9]. Percentages of complete clinical resolution of PSE, moderate improvement and lack of response were identical with the two treatments, suggesting that lactitol is as effective as lactulose in the management of patients with acute PSE. Since no statistically significant differences were found in the assessment of the neurological state after the two 3 month periods of treatment with lactulose and with lactitol, the results of the present study confirm those of the two previously reported comparisons between these two treatments [7,8] and suggest that both sugars are equally effective in chronic PSE. Neither lactulose nor lactitol provoked significant changes in the biochemical parameters analyzed, including glucose. It is important to note that the monosaccharides contained in the lactulose solution did not impair glucose metabolism in patients receiving lactulose syrup. The dosage of both sugars was easily managed in order to obtain the desired stool frequency and consistency and only two patients had diarrhea during both therapeutic periods. Although meteorism and abdominal discomfort were more frequent during lactitol treatment, the majority of patients preferred lactitol to lactulose because the taste of lactulose was found to be too sweet and provoked nausea. From the results of this study we can conclude that lactitol, given at an initial dosage of 10 g every 6 h and adjusting it subsequently to obtain soft and copious
110
m o t i o n s , p r e f e r a b l y t w o a d a y , is a g o o d a l t e r n a t i v e
D. H E R E D I A et al.
Acknowledgements
in t h e t r e a t m e n t o f p a t i e n t s w i t h c h r o n i c r e c u r r e n t P S E , e s p e c i a l l y in t h o s e w h o d o n o t t o l e r a t e t h e excessive s w e e t n e s s of l a c t u l o s e .
T h e a u t h o r s a c k n o w l e d g e Z y m a S . A . for t h e supply o f lactitol a n d M r . A l b e r t G a r c f a a n d Ms. E u l h l i a V e n t u r a for e x p e r t t y p i n g o f t h e m a n u s c r i p t .
References 1 Bown RL, Gibson JA, Sladen GE, Hicks B, Dawson AM. Effects of lactulose and other laxatives on ileal and colonic pH as measured by a radiotelemetry device. Gut 1974; 15: 999-1004. 2 Patil DH, Westaby D, Mahida YR, et al. Comparative modes of action of lactitol and lactulose in the treatment of hepatic encephalopathy. Gut 1987; 28: 255-259. 3 Zeeger R, Drinkwater JE, Fenton JCB, Vince A, Dawson AM. Some observations on the effects of treatment with lactulose in chronic hepatic encephalopathy. Q J Med 1970: 39: 245-263. 4 Bircher J, Muller J, Guggenheim P, Haemmerli UP. Treatment of chronic portal systemic encephalopathy with lactulose. Lancet 1966; i: 890-892. 5 Conn HO, Lieberthal MM. The Hepatic Coma Syndromes and Lactulose. Baltimore/London: Williams & Wilkins, 1980: 185. 6 Bircher J, Biihrer M, Franz K, Van Velthuijsen JA. Erstmalige Anwendung von Lactitol in der Behandlung der porto-systemischen Enzephalopathie. Schweiz Med Wochenschr 1982:112: 1306-1307. 7 Lanthier PL. Morgan MY. Lactitol in the treatment of chronic hepatic encephalopathy: an open comparison with lactulose. Gut 1985; 26: 415-420. 8 Morgan MY, Hawley KE. Stambuk D. Lactitol versus lactulose in the treatment of chronic hepatic encephalopathy. A double-blind, randomized, cross-over study. J Hepatol 1987; 4: 236-244. 9 Heredia D, Caballeria J. Arroyo V, Ravelli G, Rodds J. Lactilol versus lactulose in the treatment of acute portal systemic encephalopathy (PSE). A controlled trial. J Hepa-
tol 1987; 4: 293-298. 10 Conn HO, Leevy CM, Vlahcevic ZR, et al. Comparison of lactulose and neomycin in the treatment of chronic portalsystemic encephalopathy: a double blind controlled trial. Gastroenterology 1977; 72: 573-583. 11 Summerskill WHJ, Davidson EA, Sherlock S, Steiner RE. The neuropsychiatric syndrome associated with hepatic cirrhosis and an extensive portal coliateral circulation. Q J Med 1956; 25: 245-266. 12 Shafer DF, Jones EA. Hepatic encephalopathy and the gamma-aminobutyric acid neurotransmitter system. Lancet 1982: ii: 18-20. 13 James JH. Ziparo V, Jeppson B, Fischer JE. Hyperammonaemia, plasma aminoacids imbalance and blood-brain aminoacid transport: a unified theory of portal-systemic encephalopathy. Lancet 1979; ii: 772-775. 14 Fischer JE, Baldessarini RJ. Pathogenesis and therapy of hepatic coma. In: Popper H, Schaffner E, eds. Progress in Liver Diseases. New York: Grune and Stratton, 1976. 15 Crossley IR, Wardle EN, Williams R. Biochemical mechanisms of hepatic encephalopathy. C[in Sci 1983; 64: 247-252. 16 Castell DO, Moore EW. Ammonia absorption from the human colon. The role of non-ionic diffusion. Gastroenterology 1971; 60: 33-42. 17 Vince A, Killingley M, Wrong OM. Effect of lactulose on ammonia, production in a faecal incubation system. Gastroenterology 1978; 74: 544-549. 18 Patil DH, Grimble GK, Silk DBA. Lactitol, a new hydrogenated lactose derivative: intestinal absorption and laxative threshold in normal human subjects. Br J Nutr 1987; 57: 195-199.
Journal of Hepatology, 1988; 7: 106-110
Elsevier HEP 00424
Lactitol vs. lactulose in the treatment of chronic recurrent portal-systemic encephalopathy
D. H e r e d i a , J. T e r 6 s , N. O r t e u a n d J. R o d 6 s Liver Unit and Neurology Service, Hospital Clinic i Provincial. Medical School, Barcelona (Spain)
(Received 12January 1988) (Accepted 22 February 1988)
Summary To compare the efficacy and patient acceptability of lactitol vs. lactulose in chronic recurrent portal-systemic encephalopathy (PSE), 25 cirrhotic patients with a history of repeated episodes of hepatic encephalopathy who required chronic administration of lactulose were included in a controlled cross-over cli0ical trial in which patients received, at random, lactitol (at an initial dosage of 10 g/6 h) or lactulose (15 ml/6 h, 66% w/v, containing 10 g of lactulose) during a 3 month period and then crossed-over to the alternative treatment for the following 3 months. Doses were adjusted to obtain two bowel movements per day. During the study period the daily protein intake was 40-60 g. Clinical and analytical data (including ammonia levels) were obtained, an E E G and the number connection test were performed and the PSE index was determined before treatment and monthly until the end of the treatment. No significant differences were found between the effects of lactitol and lactulose on the neurological and biological parameters, suggesting that the two treatments could be considered as equally effective. Lactitol was significantly better tolerated than lactulose (P = 0.02), the taste of which was assessed as being too sweet and provoking nausea. In conclusion, lactitol is a good alternative to lactulose for patients with chronic recurrent PSE, especially in those who do not tolerate the excessive sweetness of lactulose.
Introduction Lactulose (fl-galactoside-fructose) is a synthetic disaccharide that is not absorbed in the small bowel and produces a cathartic effect and a decrease in intraluminal pH when it reaches the right [1,2] colon. Lactulose has been the treatment of choice of portalsystemic encephalopathy (PSE) [3] since it was intro-
duced in 1966 [4]. This substance has, however, some disadvantages, mainly its contamination with other sugars such as galactose and fructose, which theoretically may impair glucose metabolism in cirrhosis [5]. This effect is, however, irrelevant, since in commercial preparations of lactulose syrup the maximum contamination with monosaccharides is less than 15%, each 15 ml dose of syrup thus usually contain-
Correspondence: Dr. J. Ter6s, Servicio de Hepatologia, Hospital Clinic i Provincial, Villarroel, 170, 08036 Barcelona, Spain.
0168-8278/88/$03.50 (~) 1988 Elsevier Science Publishers B.V. (Biomedical Division)
LACTITOL VS. LACTULOSE IN PSE
107
ing about 2 g of monosaccharides. A n o t h e r disadvantage of lactulose is its excessively sweet taste that may provoke aversion and nausea in some patients, especially in those with chronic recurrent PSE who need long-term therapy with this compound. In some European countries lactulose is also available as a chemically pure white crystalline powder which is less sweet than the syrup. Recent investigations [6-9] suggest that lactitol, a soluble disaccharide (fl-galactoside-sorbitol) with effects similar to those of lactulose, may be useful in the treatment of PSE in cirrhotics. Lactitol is supplied as a chemically pure white crystalline powder with a mildly sweet taste. The aim of the present study was to compare the efficacy of and tolerance to lactitol and lactulose in cirrhotic patients needing long-term treatment.
Patients and Methods
Twenty-five cirrhotic patients with chronic or recurrent PSE requiring long-term therapy with lactulose were included in the study. Cirrhosis was documented in all cases by means of needle or surgical biopsy. Fifteen patients were alcoholics, whereas in the remaining cases the etiology of cirrhosis was considered posthepatitic in six and cryptogenic in four. TABLE 1 BIOCHEMICAL DATA OF PATIENTS AT ENTRY INTO THE STUDY
Hemoglobin (g/dl) Platelets (103/ml) Quick (%) NH4 (/tmol/100 ml) Total protein (g/I) Albumin (g/I) Glucose (mg/dl) Alkaline phosphatase (U/I)~ Bilirubin (mg/dl) Aspartate aminotransferase (U/I)b y-Glutamyltransferase (U/I)¢
Mean S.D.
Minimum Maximum
12 2.12 115 51 65.7 17.34 154.3 41.2 72.8 8.1 32.9 4.4 107.3 51.8
9.10 53 45 86.7 58 26 72
15.70 250 100 225.3 88 42 292
342.5 261.8 2.8 3.9
70 0.8
984 17.3
10
280
9
646
85.3
70.2
126.4 201
Normal values: a280 U/l; b40 U/l; c40 U/I.
All patients had had a portal-systemic shunt because of variceal bleeding between 1 and 7 years before their inclusion in the study, and all had clinical evidence of repeated episodes of PSE and had been treated with iactulose during a period of at least 3 months before the study. Patients with advanced hepato-renal syndrome or liver cell carcinoma were not included in the study. After giving their informed consent, patients were randomly allocated, following a random number table, to treatment with either lactulose or lactitol, without a washout period. Patients were put on a standard diet with a protein content of 40-60 g, and no other treatment for PSE was allowed during the study. Lactulose was administered as a syrup at an initial dosage of 15 ml (66% w/v; 15 ml of syrup contains 10 g of lactulose) every 6 h, and lactitol as a powder at a dosage of 10 g every 6 h. Dosages of both compounds were adjusted with the aim of procuring two soft bowel movements per day. After 3 months, patients were crossed-over to the alternative treatment for a second 3 month period, without a washout period. Before the beginning of the treatment and every month during the 6 months' duration of the study, patients were visited by the same physician (D.H.) in the outpatients department and underwent a physical and neurological examination, electroencephalogram ( E E G ) and a battery of biochemical tests (Table 1). PSE sum and PSE index were calculated according to Conn et al. [10]. Qualitative variables were evaluated in a semiquantitative way according to the following scale: 0 = normal, 1 = mildly abnormal, 2 = markedly abnormal, 3 = severely abnormal. During the whole period of treatment, patients filled in a questionnaire with daily dosage, stool frequency and consistency, acceptability of the compound (graded as 1 = very poor, 2 = poor, 3 = mild, 4 = very good), side effects and other phenomena, if any. The comparison of efficacy of lactitol and iactulose was made by paired tests, Student for normally distributed variables and Wilcoxon for ordinal variables, for the results obtained at month 3 and month 6 after a 3 month period of treatment with lactitol or lactulose. This study was approved by the Ethics and
108
D. HEREDIA et al.
TABLE 2
TABLE 3
QUANTIFIED NEUROLOGICAL STATE AT ENTRY INTO THE STUDY, AFTER 3 MONTHS OF LACTITOL AND AFTER 3 MONTHS OF LACTULOSE
TOLERANCE TO LACTITOL AND LACTULOSE
At entrya Flapping Consciousness Memory Intellect Speech Handwriting Sum PSE PSEindex
0.95 + 0.82 0.45 + 0.60 1.05 + 0.68 0.55 + 0.60 1.5 + 0.57 1.15 + 1.03 7.25+3.3 25.9+ 11.8
After lactitol
After lactulose
Side effect
a All patients on entry were under lactulose therapy when they underwent neurological examination. Research C o m m i t t e e of the Hospital Clinic i Provincial.
Results
Five of the 25 patients had to be excluded from the trial. One of them died after the first visit from pneumonia and sepsis and a n o t h e r after the second visit from gastrointestinal bleeding. The remaining three patients d r o p p e d out during the follow-up, one after the first visit and two after the second visit. F o u r t e e n of the 20 patients analyzed were male and six female. Mean age was 54.5 + 2.1 years and the mean duration of the disease at the beginning of the treatment was 2.5 + 2 years. All patients with alcoholic cirrhosis claimed to have s t o p p e d drinking after the portal-systemic shunt. Two-thirds of the patients had flapping t r e m o r when they e n t e r e d the study and seven had ascites. Quantified neurological state before the start of the study is shown in the first column of Table 2 and the results of biochemical tests in Table 1. The mean daily dosages required to obtain two bowel m o v e m e n t s per day were 60 --- 29.4 ml of lactulose syrup (containing 40.2 + 19.6 g of lactulose) and 35.6 + 17.5 g of lactitol. No statistically significant differences were found in the assessment of the neurological state, as shown in Table 1, or in the biological data between the two therapeutic periods (lactulose or lactitol). Venous
Lactulose
cases mentions cases mentions
P
1.15 + 0.87 1 + 0.56 0.42 0.65 + 0.58 0.4 + 0.5 0.76 1.4 + 0.59 1.15 + 0.67 0.55 0.7 + 0.73 0.75 + 0.55 0.75 1.45 + 0.68 1.5 + 0.68 0.52 1.05 + 0.88 1.1 + 0.78 0.44 7.19+2.8 8.12+5.3 0.49 25.7+9.9 29+ 19.1 0.49
Lactitol
Meteorism Nausea Abdominal discomfort Too-sweet taste Dyspepsia Gastric acidity Diarrhea
6 0 3 0 0 I 2
11 6 1 2
2 4 2 7 1 0 2
2 5 2 12 1 2
blood a m m o n i a level was 152.09 + 31.57 ~mol/100 ml after lactulose and 140.66 + 44.87~mol/100 ml after lactitol (t = 1.20, n.s.). B l o o d glucose levels did not change significantly either after lactulose (before: 107.4 + 44.6 mg/dl, after: 114 ___67.9 mg/dl, t = 0.78, n.s.) or after lactitol (before: 99.2 + 24.8 mg/dl, after: 114.(~ + 62.3 mg/dl, t = - 1 . 3 4 , n.s.). With regard to the data r e c o r d e d by the patient, there were no differences between the two treatments in stool frequency (1.65 + 0.6 for lactitol and 1.57 + 0.63 for lactulose) and consistency. M o r e than half the patients achieved the two desired soft motions a day with the two sugars. The remaining patients had only one motion a day, but soft and copious. Acceptability was b e t t e r for lactitol than for lactulose (Wilcoxon test, z = -2.1917, P = 0.02), the taste of which was assessed as being too sweet and provoking nausea. M e t e o r i s m and a b d o m i n a l discomfort were slightly m o r e frequent with lactitol than with lactulose (Table 3). No adverse reactions leading to withdrawal were observed with either of the treatments.
Discussion
PSE is a frequent complication of cirrhosis of the liver, especially in patients who have large spontaneous or surgical portal-systemic shunts [11]. Although diverse metabolic disorders have been recently implicated in the pathogenesis of PSE [12-15], the classic hypothesis of the passage to the general circulation of toxic nitrogenous substances, mainly
LACTITOL VS. LACTULOSE IN PSE ammonia, formed in the intestine by bacterial action on proteins remains widely accepted. Favoring this hypothesis, the most effective treatment of PSE is directed towards reducing the intestinal production and absorption of these toxic substances [5]. Lactulose was introduced in the therapy of PSE in 1966 by Bircher et al. [4] and it is, at present, the treatment of choice for this complication. The mechanism by which this substance improves PSE is uncertain. Lactulose is a synthetic disaccharide, derived from lactose, which is not absorbed in the bowel due to the lack of an appropriate disaccharidase in the human intestinal mucosa. Therefore, it is unchanged upon reaching the lower bowel where it is broken down by bacteria producing volatile fatty acids (acetic, propionic, butyric and lactic) [2]. Classically it has been suggested that lactulose improves PSE due to its laxative properties, and also because the reduction of the intraluminal pH induced by the bacterial transformation of lactulose would favor the conversion of ammonia imo ammonium, which is almost incapable of passing through the intestinal wall [16]. A complementary hypothesis is that lactulose may provide a carbohydrate source to facilitate ammonia utilization by gut bacteria [17]. In 1982, Bircher et al. [6] successfully treated a patient with a portacaval shunt and chronic PSE with lactitol. Lactitol is also a synthetic disaccharide (/3galactoside-sorbitol) that is synthesized almost pure in chrystalline form and is soluble in water at 25 °C. It can be supplied as a powder or tablets and its taste is less sweet than that of lactulose. The mechanism by which lactitol improves PSE is probably similar to that of lactulose, since it is not absorbed by the small intestine and is broken down by colonic bacteria [2,18]. Since the first experience of Bircher et al. [6], lactitol has been compared with lactulose in three published investigations. One of them [7] was an open comparison in five patients suffering from chronic PSE that had been treated for 3 month periods with lactulose and lactitol. This study showed that lactitol was at least as efficacious as lactulose 'but was more acceptable because its cathartic effect was more predictable, its formulation was more convenient and its
109 less sweet taste preferred'. Recently, Morgan et al. [8] published the results of a randomized, cross-over comparison between lactitol and lactulose in which both sugars were administered as a solution, identical in taste and appearance and with similar physicochemical properties. Twelve patients requiring longterm treatment for PSE were treated for periods of 3 months with each sugar in a double-blind form. From this study the authors concluded that the treatments were equally effective in the treatment of chronic PSE and that the incidences of side effects were not statistically different. Finally, we compared lactulose and lactitol in a series of 40 cirrhotic patients with an acute episode of PSE who were randomly treated with one of the two sugars [9]. Percentages of complete clinical resolution of PSE, moderate improvement and lack of response were identical with the two treatments, suggesting that lactitol is as effective as lactulose in the management of patients with acute PSE. Since no statistically significant differences were found in the assessment of the neurological state after the two 3 month periods of treatment with lactulose and with lactitol, the results of the present study confirm those of the two previously reported comparisons between these two treatments [7,8] and suggest that both sugars are equally effective in chronic PSE. Neither lactulose nor lactitol provoked significant changes in the biochemical parameters analyzed, including glucose. It is important to note that the monosaccharides contained in the lactulose solution did not impair glucose metabolism in patients receiving lactulose syrup. The dosage of both sugars was easily managed in order to obtain the desired stool frequency and consistency and only two patients had diarrhea during both therapeutic periods. Although meteorism and abdominal discomfort were more frequent during lactitol treatment, the majority of patients preferred lactitol to lactulose because the taste of lactulose was found to be too sweet and provoked nausea. From the results of this study we can conclude that lactitol, given at an initial dosage of 10 g every 6 h and adjusting it subsequently to obtain soft and copious
110
m o t i o n s , p r e f e r a b l y t w o a d a y , is a g o o d a l t e r n a t i v e
D. H E R E D I A et al.
Acknowledgements
in t h e t r e a t m e n t o f p a t i e n t s w i t h c h r o n i c r e c u r r e n t P S E , e s p e c i a l l y in t h o s e w h o d o n o t t o l e r a t e t h e excessive s w e e t n e s s of l a c t u l o s e .
T h e a u t h o r s a c k n o w l e d g e Z y m a S . A . for t h e supply o f lactitol a n d M r . A l b e r t G a r c f a a n d Ms. E u l h l i a V e n t u r a for e x p e r t t y p i n g o f t h e m a n u s c r i p t .
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