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Role of fructose-sorbitol malabsorption in the irritable bowel syndrome
GASTROENTEROLOGY
1990;99:1016-1020
Role of Fructose-Sorbitol Malabsorption in the Irritable Bowel Syndrome G. FRITZ NELIS,
MARJA A. P. VERMEEREN,
Department
Sophia Ziekenhuis Zwolle. The Netherlands
of Medicine,
Because even after low dO6e6of fructose and sorbitol, fructose-sorbitol malabsorption has been found in a high number of patients with the irritable bowel syndrome, an etiological role of fructose-sorbitol malabsorption in the irritable bowel syndrome has been suggested. However, these studies have been uncontrolled. Therefore, a controlled study of fructose-sorbitol malabsorption in the irritable bowel syndrome compared with healthy controls was performed. Seventy-three patients, 23 men and 50 women with a mean age 43.1 f 1.7 years (range, 18-88 years) with the irritable bowel syndrome were compared with 87 age- and sex-matched control subjects. Fructose-sorbitol malabsorption was determined by a breath-hydrogen test (Lactoscreen, Hoek Loos, Schiedam, The Netherlands) following an oral load of 25 g fructose and 5 g sorbitol after a IO-hour fast. Fructose-sorbitol malabsorption, as shown by an H, peak of 20 ppm over basal values, was found in 22 (30.1%) of the patients and 35 (40.2%) of the control subjects. With a lower peak level of 10 ppm over basal values, these percentages were 45.2% and 57.5%, respectively. Also, the highest H, peak values (15.2 t 2.3 ppm vs. 21.5 f 2.8 ppm), time to reach peak levels (110.7 + 5.4 min vs. 107.1 + 5.9 min), and area under the H, curve (1310 + 219 ppm - min vs. 1812 + 255 ppm - min) did not discriminate between patients and controls. During the test, symptoms developed in 31 of 70 patients and in 3 of 85 control subjects (P =E0.0001). Symptomatic patients did not differ from asymptomatic patients regarding the presence or absence of fructose-sorbitol malabsorption, H, peak values, and area under the curve. No differences could be identified between male and female patients or controls. In conclusion, fructosesorbitol malabsorption is frequently seen in patients with irritable bowel syndrome, but this is not different from observations in healthy volunteers. Therefore, fructose-sorbitol malabsorption does not seem to play an important role in the etiology of irritable bowel syndrome.
and WIM JANSEN
S
orbit01 has been widely used as a sweetener in sucrose-free dietary products since its introduction in 1929 (1). The first study on sorbitol-induced diarrhea was reported by Gryboski (2), who described an infant’s watery diarrhea caused by dietetic candies containing 9.3 g of sorbitol. A subsequent analysis showed sorbitol malabsorption in children aged t3 years, while absorption improved in older children (2). In adults chewing gum, diarrhea has been incidentally described after large quantities of sorbitol were used during weight reduction regimens (34. The diarrheainducing capacity of sorbitol has been used in radiology for bowel preparation (5) and in combination with lactulose in the treatment of portal-systemic encephalopathy [S). Because of its lower glycemic index, fructose has been advocated to replace glucose and sucrose in diabetic diets. Although the maximum fructose absorption capacity can be as great as 4800 g/day if administered continuously (7), single doses of 50 g can surpass the maximal absorption capacity (8-10). Fructosesorbitol malabsorption (FSM) occurs more frequently at lower combined doses of fructose and sorbitol than in separate doses (111. There are incidental reports of irritable bowel syndrome (IBS) symptoms subsiding on fructose-free diets (12). Recently it has been suggested that FSM may play a role in the etiology of IBS (13). However, fructose malabsorption was only identified in a minority of IBS patients, and FSM has not been investigated in all of them. Because FSM in IBS was not investigated systematically and not compared with control subjects, this study compares FSM in a large group of IBS patients and in control subjects.
Abbreviations usedin this paper:AIJC,areaunder the curve; ~~erythrocytesedimentationrate;FSM,fructosesorMtol~~ sorption;IBS,irritablebowel~~me. Ol99ObytheAmedcanGaatroenterologicalAssodation 00%5065/90/$3.00
ETIOLOGICAL
October 1990
Materials and Methods The investigation was performed in 73 consecutive outpatients (23 men, 50 women) aged 43.1 + 1.66 years (range, 16-66 years] with IBS symptoms lasting for more than 1 year. The patients were compared with 87 age- and sex-matched control subjects (25 men, 62 women] aged 37.9 * 0.9 years (range, 17-54 years). All patients had received diagnoses of IBS based on clinical criteria, and organic gastrointestinal disease had been excluded on previous occasions. Each patient had undergone at least a complete physical examination; full blood count; erythrocyte sedimentation rate (ESR); liver function tests; stool analysis for parasites, ova, and blood; and a sigmoidoscopy. Patients were recruited for this study only if they had diagnostic scores >44 points according to the criteria defined by Kruis et al. (14). Before the present investigation, complete histories and physical examinations were repeated, and laboratory examinations and sigmoidoscopy were repeated if more than 12 months had elapsed since the original examinations. The patients were assigned scores according to their main symptoms: pain-predominant, 41; constipation-predominant. 13; bloating-predominant, 12; and diarrhea-predominant. 7. Control subjects were selected from the hospital staff. None of the control subjects had abdominal symptoms, had been investigated for gastrointestinal diseases in the past, or had a history of serious illness. All control subjects had normal and regular bowel habits. Reasons for exclusion in both patients and controls included previous abdominal operations; previous organic gastrointestinal disease; disturbance of cardiorespiratory, hepatic, renal, or endocrinologic function; and the use of antibiotics or any other drug in the previous month. None of the patients or control subjects had a history of specific food intolerance or food allergy. Patients and control subjects were examined after an overnight fast of at least 10 hours. During the whole test period, all subjects continued fasting and refrained from smoking. All subjects were asked whether they had symptoms during the test. Fructose-sorbitol malabsorption was investigated by breath hydrogen testing in end-respiratory air samples that were collected in a 50-mL plastic syringe (15). After obtaining two basal samples at a &minute interval, the arithmetic mean was considered to be the basal H, excretion. Directly after obtaining the basal samples, an oral load of 25 g fructose and 5 g sorbitol dissolved in 150 mL tap water was given orally within 1 minute. This dose was chosen in analogy to previous studies (10~1~3). Breath samples were taken at 30-minute intervals for 3 hours and immediately analyzed. In these samples, hydrogen was analyzed by HZ-sensitive conductance using a Lactoscreen H, breath tester manufactured by Hoek Loos (Schiedam, The Netherlands) which has a range of o-200 ppm and an accuracy of *2%. Previously this method has been shown to have an excellent correlation with the gaschromatographic method (16). An increase of 20 ppm over basal values was regarded as evidence of FSM (9). The peak value of H, excretion above basal excretion (H,,,,) in ppm, the time to reach peak values (tH,,. in minutes, and the area under the curve of H, excretion above basal values (AU&,) in ppm - min were determined
ROLE OF FSM IN IBS PATIENTS
1017
considering the IBS and control group as a whole and only considering subjects with Hhnax >lO ppm and >20 ppm, respectively. Patients and control subjects were regarded as constitutional non-H, producers if no H, was expired after both the test solution and subsequent testing with 50 g la&dose.
During the whole test period, symptoms of bowel cramps, diarrhea, and flatulence were scored in patients and control subjects with the following scoring system: 0, absent; 1, minor (temporarily interfering with activities]: 2, moderate (all activities to be discontinued); 3, severe (needs to lie down). The proportions of malabsorbers in the IBS and control groups and the presence of symptoms during the test in either group were compared using the x2 test and Fisher’s exact test. Comparisons of Hamax,tHZmax,and AU&, were made with the Wilcoxon rank-sum test at a confidence level of +5%. All results are expressed as mean f SEM. The study was conducted in accordance with the Declaration of Helsinki-Tokyo and approved by the local ethical committee. All subjects gave written informed consent to participate in the study.
Results Three of 73 IBS patients and 2 of 87 control subjects were constitutional non-H, producers and were disregarded for analysis, leaving 70 patients and 85 control subjects suitable for evaluation. The mean values and SEM of H, excretion at any interval are shown in Table 1. At a cutoff level of HPmax20 ppm over basal values, 22 of 70 patients (31.4%) and 35 of 85 controls (41.5%) had FSM (P > 0.05). Thirty-three (47.1%) IBS patients and 50 (59.4%) controls had H,, more than 10 ppm over basal values (P > 0.05) (Table 2). The HBmaxwas 15.2 f 2.3 ppm in IBS patients and 21.5 f 2.6 ppm in controls, and the tH,,, was 110.7 + 5.4 minutes in IBS patients and 107.1 f 5.9 minutes in controls (P > 0.05). For subjects excreting more than 20 ppm H, above basal values, the H,, was 37.4 + 4.0 ppm in IBS patients and 41.7 * 3.4 ppm in controls, and the tHzmaxwas 109.5 + 7.6 minutes and 93.0 3t 7.2 minutes, respectively. For subjects excreting more than 10 ppm over basal values, the HPmaxwas 28.6 -c 3.4 ppm in patients and 31.3 + 3.1 ppm in controls, and the
Table 1. Breath Hydrogen (ppm) at 0,30,60,9O,X?O,l50, and 180 Minutes After Fructose-Sorbitol Loading 0
Patients Mean
SEM Control subjects Mean
SEM
30
3.22 4.96 0.62 0.88
60
90
120
150
180
9.22 12.66 11.00 11.49 0.38 1.53 1.88 1.59 1.79 1.14
3.89 6.34 15.63 16.67 15.52 12.12 11.50 0.53 1.11 2.05 2.41 1.64 1.66 1.42
1018
NELIS ET AL.
GASTROENTEROLOGY
Malabsorption in Patients and Control Subjects at Cutoff Levels of HSmax 20 ppm and 10 ppm Above Basal Values
Table 2. Fructose-Sorbitol
Patients (n = 70)
No.Hmax> 20 ppm (%) No. %ax
> 10 ppm
Controls In = 851
22
35 41.5 50 59.4
31.4 33 47.1
(%)
tH Pmax was 112.9 + 6.7 minutes and 104.7 + 6.9 minutes, respectively. The AUC,, was 1310 + 219 ppm - min in IBS patients and 1812 - 255 ppm - min in control subjects. The AU&. was 3467 & 414 ppm . min in IBS patients and 3610 t 418 ppm - min in controls if only subjects excreting more than 20 ppm over basal values were considered, and the values were 2583 + 335 ppm - min in patients and 2709 + 331 ppm - min in controls considering subjects with peak values 10 ppm above basal values (Table 3). Male and female IBS patients were comparable as to the presence of FSM (7 of 23 vs. 25 of 471, Hlmax (12.9 * 3.3 vs. 16.6 & 3.0) and AUC,, (1224 + 392 vs. 1331 + 267). Thirty-one of 70 patients developed symptoms during the test period (mean symptom score, 1.34) while only 3 of 85 control subjects developed symptoms. This difference is statistically significant (P < 0.0001). Of the 31 patients with symptoms, 23 had mild, 5 had moderate, and 3 had severe symptoms. Symptoms consisted of predominantly cramps in 12, predominantly diarrhea or flatulence in 9, and both in 10. Cramps were accompanied by nausea in 8 patients. Two control subjects had minor bowel cramps and one had moderate diarrhea. The control subject who developed diarrhea had a very high Hsmaxof 133 ppm over basal values. Symptoms were present in 19 of 50 female and 12 of 23 male patients (P > 0.05). Fructose-sorbitol malabTable 3. Hzmax(ppm), tHzmax[min), and ALJCa2[ppm . min)
in Patients and Control Subjects H *max Patients All H *max> 10 ppm %l,X > 20 ppm
Symptomatic Asymptomatic Controls All HZmax > 10~~ H zmaxz 20 ppm
15.2 + 28.6 k 37.4 + 20.3 f 10.5 +
tH,,,x
AU%,
2.3 3.4 4.0 4.2 1.9
110.7 t 5.4 112.9 + 6.7 109.5 + 7.6
1310 2583 3467 1800 844
21.5 + 2.6 31.3 + 3.1 41.7 + 3.4
107.1 * 5.9 104.7 + 6.9 93.0 + 7.2
1812 + 255 1708 + 331 3610 + 418
NOTE. All values are mean r SEM.
+ + + + f
219 335 414 399 207
Vol. 99, No. 4
sorption at the 20-ppm level was present in 12 of 31 patients with symptoms and in 7 of 38 patients without symptoms (P = 0.11). At the lo-ppm level, FSM was present in 16 of 31 and 13 of 38, respectively (P = 0.21). In patients with symptoms, the Hzmaxwas 20.3 f 4.2 ppm (95% confidence limits between - 26 and +66.8) and the AU&, was 1800 + 399 ppm - min (95% confidence limits between - 2537 and +6163); and in patients without symptoms, the Hlmax was lo.5 + 1.9 ppm (95% confidence limits between - 11.5 and +33.3) and the AUCu, was 844 + 207 ppm . min (95% confidence limits between - 1443 and +3249) (P > 0.05).
Discussion In this study, we have shown that FSM is not more frequent in IBS patients than in control subjects. Hitherto, this is the first investigation dealing with FSM in IBS patients compared with an age- and sex-matched control group. The etiology of the IBS remains unknown. Psychogenic factors (17-19), motor disturbances (2O-2l), and food intolerance (l2,22) have been implicated as causes, but the condition is probably multifactorial. Based on incidental reports (12) and the finding that FSM measured by the breath H, test is found in a proportion of IBS patients, Rumessen and GudmandHoyer suggested that FSM is a factor in the etiology of IBS or IBS-like symptoms (13). Using H, breath testing in studying carbohydrate absorption, a 2%ppm increase of breath H, excretion over basal values is generally accepted (9,23,24). However, some authors have suggested that a lo-ppm increase may already be indicative of FSM (13,251. Therefore, we evaluated our results at both 20-ppm and lo-ppm cutoff levels. At a conventional level of a ZO-ppm increase of H, production, 9 of 25 IBS patients in the study of Rumessen and Gudmand-Hoyer showed evidence of malabsorption: at the lower cutoff level of 10 ppm, 13 of 25 showed malabsorption. These 13 patients were investigated for sorbitol malabsorption, which was present in 4 of them after a 5-g sorbitol load. Twelve of the 13 patients had malabsorption for the combined administration of 25 g fructose and 5 g sorbitol, which represents 36% and 52% of the total group using the respective cutoff levels of a 20-ppm and lo-ppm increase. The 12 patients not showing malabsorption of 25 g fructose were excluded from further analysis (13). However, in previous studies, the same authors showed malabsorption of 25 g fructose in 50% and malabsorption of 5 g sorbitol in 60% of healthy controls (9,10), and their study of IBS patients did not contain a control group. Hyams showed malabsorption of 5 g sorbitol in 4 of 7 healthy subjects (26).
October 1996
In this controlled study, FSM was found in 22 of 70 (31.4%) IBS patients and in 35 of 85 (41.5%) age- and sex-matched control subjects using the conventional cutoff level of Hzmax20 ppm over basal values and in 33 of 70 (47.1%) IBS patients and 50 of 85 (59.4%) controls using the lower cutoff level of 10 ppm increase over basal values. These percentages are in the same range for both healthy volunteers and IBS patients as found in uncontrolled studies by the other authors (13,26). Therefore, in our study FSM was not more frequently observed among IBS patients than among controls at either cutoff level. Also if quantative parameters of FSM (Hamax,tHzmau, and AUC,,) were measured, we did not find differences between patient and control groups as a whole, or in the subgroups with FSM measured at 20-ppm and lo-ppm levels (Table 3). The most frequent clinical symptom in the IBS group was abdominal pain. Patients with diarrhea-predominance were a minority in our study group, but did not differ from the other clinical subgroups. In Rumessen’s study of 25 IBS patients, 2 were male and 23 were female. Our study group, with 23 male and 50 female subjects, is more in accordance with the sex ratio of 1:2-3 reported in the literature (27). We did not find FSM to be more frequent in male or female subjects in either the patient group or the controls. In the IBS group, significantly more subjects developed symptoms during fructose-sorbitol loading than in the controlgroup (P < 0.0001). Because the presence or absence of FSM, Hgmax,or AUC,, did not significantly differ in asymptomatic patients, symptomatic patients, and control subjects, the development of symptoms is not readily explained by measurable differences in intestinal fructose-sorbitol handling. In patients developing symptoms during the test, fructosesorbitol probably constitutes an atypical stimulus to an irritated bowel system. It has been shown previously that IBS patients develop symptoms during balloon inflation of the colon at lower thresholds than control subjects (28) and are more prone to react to a variety of somatic stimuli (29,301. This probably reflects Read’s hypothesis of the hypersensitive gut (31) and is no evidence of an abnormality in fructose-sorbitol absorption. Therefore, we conclude that FSM does not play a role in the etiology of the IBS.
References 1. VonNoorden KH. Sionon in der Diabetesbehandlung. Deutsch Med Wochenschr 1929;55:483. 2. Gryboski JD. Diarrhea from dietetic candies. N Engl J Med 1966;275:718. 3. Ravry MJR. Dietetic food diarrhea. JAMA 1980;244:270.
ETIOLOGICAL ROLE OF FSM IN IBS PATIENTS
1019
4. Goldberg LD, Ditchek NT. Chewing gum diarrhea. Am J Dig Dis 1978;23:568. 5. Pochaczevsky R. Oral examination of the colon: “the colonic cocktail.” Am J Roentgen01 1974;121:318-325. 6. Levinsky NG, Alexander EA. Acute renal failure. In: Brenner BM, Rector FC, eds. The Kidney. Volume 2. Philadelphia: Saunders, 1976:806-837. 7. Crane RK. The physiology of the intestinal absorption of sugars. In: Jeannes A, Hodges J, eds. Physiological effects of food carbohydrates. Washington: American Chemical Society, 1975: 2-19. 8. Groen J. The absorption of hexoses from the upper part of the small intestine in man. J Clin Invest 1937:16:245-255. 9. Ravich WJ, Bayless TM, Thomas M. Fructose: incomplete intestinal absorption in humans. Gastroenterology 1983:84:2629. 10.Rumessen JJ, Gudmand-Hoyer E. Absorption capacity of fructose in healthy subjects. Comparison with sucrose and its constituent monosaccharides. Gut 1986;27:1161-1168. 11. Rumessen JJ, Gudmand-Hoyer E. Malabsorption of fructosesorbitol mixtures; interactions causing abdominal distress. Stand J Gastroenterol1987;22:431-436. 12.Andersson DEH, Nygren A. Four cases of long-standing diarrhoea and colic pains cured by fructose-free diet. A pathogenetic discussion. Acta Med Stand 1978;203:87-92. 13.Rumessen JJ, Gudmand-Hoyer E. Functional bowel disease: malabsorption and abdominal distress after ingestion of fructose, sorbitol and fructose-sorbitol mixtures. Gastroenterology 1988:95:694-700. 14.Kruis W, Thieme G. Weinzierl M, Schussler P, Ho01 J. Paulus W. A diagnostic score for the irritable bowel syndrome. Its value in exclusion of organic disease. Gastroenterology 1984;87:1-7. 15.Metz G. A simple method of measuring breath hydrogen in carbohydrate malabsorption by end expiratory sampling. Clin Sci Med 1976;50:237-240. 16.Douwes AC, Fernandes J. Degenhart HJ. Improved accuracy of lactose tolerancy test in children using expired H, measurements. Arch Dis Child 1978;53:939-942. 17. Almy T, Hinkle L, Burke B, Kern F. Alterations in colonic function in men under stress. Gastroenterology 1949;12:437-449. 18.Waller SL, Misiewicz JJ. Prognosis in irritable bowel syndrome. Lancet 1969;2:753-756. 19. Ealer MD, Goulston KJ. Levels of anxiety in colonic disorders. N EnglJ Med 1973;288:16-20. 20.Schuster MM, Whitehead WE. Physiologic insights into irritable bowel syndrome. Ballieres Clin Gastroenterol 1986;15:839-853. 21. Drossman DA, Lowman BC. Irritable bowel syndrome: epidemiology, diagnosis and treatment. Baillieres Clin Gastroenterol 1985;14:559-573. 22. Alun Jones V, Shorthouse M, McLaughlan P, Workman E. Hunter JO. Food intolerance: a major factor in the pathogenesis of irritable bowel syndrome. Lancet 1982;2:1115-1117. 23. Metz G, Jenkins DJ, Peters TJ. Breath hydrogen as a diagnostic method for hypolactasia. Lancet 1975;1:1155-1157. 24. Roman0 TJ, Dobbins JW. Evaluation of the patient with suspected malabsorption. Gastroenterol Clin North Am 1989;18:467484. 25.Barr RG, Watkins JB, Perman JA. Mucosal function and breath hydrogen excretion: comparative studies in the clinical evaluation of children with nonspecific abdominal complaints. Pediatrics 1981:68:526-533. 26.Hyams JS. Sorbitol intolerance: an unappreciated cause of functional gastrointestinal complaints. Gastroenterology 1983;84: 30-33. 27.Grant Thompson W. The irritable bowel. Gut 1984;25:305-320.
1020 NELIS ET AL
28. Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the irritable bowel syndrome. Gut 1973;14:125-132. 29. Whitehead WE, Engel BT, Schuster MM. Irritable bowel syndrome. Physiological and psychological differences between diarrhea-predominant and constipation-predominant patients. Dig Dis Sci 1980;25:404-413. 30. Fielding JF. Clinical spectrum of the irritable bowel syndrome. Baillieres Clin Gastroenterol1977;6:607-622.
GASTROENTEROLOGY
Vol. 99, No. 4
31.Read NW. Irritable bowel syndrome (IBS)-definition and pathophysiology. Stand J Gastroenterol1987;13O(Suppl):7-13.
Received December 21,1989. Accepted April 16,199O. Address requests for reprints to: G. F. Nelis. M.D., Ph.D., Sophia Ziekenhuis PO 10400,800O GK Zwolle, The Netherlands.
1990;99:1016-1020
Role of Fructose-Sorbitol Malabsorption in the Irritable Bowel Syndrome G. FRITZ NELIS,
MARJA A. P. VERMEEREN,
Department
Sophia Ziekenhuis Zwolle. The Netherlands
of Medicine,
Because even after low dO6e6of fructose and sorbitol, fructose-sorbitol malabsorption has been found in a high number of patients with the irritable bowel syndrome, an etiological role of fructose-sorbitol malabsorption in the irritable bowel syndrome has been suggested. However, these studies have been uncontrolled. Therefore, a controlled study of fructose-sorbitol malabsorption in the irritable bowel syndrome compared with healthy controls was performed. Seventy-three patients, 23 men and 50 women with a mean age 43.1 f 1.7 years (range, 18-88 years) with the irritable bowel syndrome were compared with 87 age- and sex-matched control subjects. Fructose-sorbitol malabsorption was determined by a breath-hydrogen test (Lactoscreen, Hoek Loos, Schiedam, The Netherlands) following an oral load of 25 g fructose and 5 g sorbitol after a IO-hour fast. Fructose-sorbitol malabsorption, as shown by an H, peak of 20 ppm over basal values, was found in 22 (30.1%) of the patients and 35 (40.2%) of the control subjects. With a lower peak level of 10 ppm over basal values, these percentages were 45.2% and 57.5%, respectively. Also, the highest H, peak values (15.2 t 2.3 ppm vs. 21.5 f 2.8 ppm), time to reach peak levels (110.7 + 5.4 min vs. 107.1 + 5.9 min), and area under the H, curve (1310 + 219 ppm - min vs. 1812 + 255 ppm - min) did not discriminate between patients and controls. During the test, symptoms developed in 31 of 70 patients and in 3 of 85 control subjects (P =E0.0001). Symptomatic patients did not differ from asymptomatic patients regarding the presence or absence of fructose-sorbitol malabsorption, H, peak values, and area under the curve. No differences could be identified between male and female patients or controls. In conclusion, fructosesorbitol malabsorption is frequently seen in patients with irritable bowel syndrome, but this is not different from observations in healthy volunteers. Therefore, fructose-sorbitol malabsorption does not seem to play an important role in the etiology of irritable bowel syndrome.
and WIM JANSEN
S
orbit01 has been widely used as a sweetener in sucrose-free dietary products since its introduction in 1929 (1). The first study on sorbitol-induced diarrhea was reported by Gryboski (2), who described an infant’s watery diarrhea caused by dietetic candies containing 9.3 g of sorbitol. A subsequent analysis showed sorbitol malabsorption in children aged t3 years, while absorption improved in older children (2). In adults chewing gum, diarrhea has been incidentally described after large quantities of sorbitol were used during weight reduction regimens (34. The diarrheainducing capacity of sorbitol has been used in radiology for bowel preparation (5) and in combination with lactulose in the treatment of portal-systemic encephalopathy [S). Because of its lower glycemic index, fructose has been advocated to replace glucose and sucrose in diabetic diets. Although the maximum fructose absorption capacity can be as great as 4800 g/day if administered continuously (7), single doses of 50 g can surpass the maximal absorption capacity (8-10). Fructosesorbitol malabsorption (FSM) occurs more frequently at lower combined doses of fructose and sorbitol than in separate doses (111. There are incidental reports of irritable bowel syndrome (IBS) symptoms subsiding on fructose-free diets (12). Recently it has been suggested that FSM may play a role in the etiology of IBS (13). However, fructose malabsorption was only identified in a minority of IBS patients, and FSM has not been investigated in all of them. Because FSM in IBS was not investigated systematically and not compared with control subjects, this study compares FSM in a large group of IBS patients and in control subjects.
Abbreviations usedin this paper:AIJC,areaunder the curve; ~~erythrocytesedimentationrate;FSM,fructosesorMtol~~ sorption;IBS,irritablebowel~~me. Ol99ObytheAmedcanGaatroenterologicalAssodation 00%5065/90/$3.00
ETIOLOGICAL
October 1990
Materials and Methods The investigation was performed in 73 consecutive outpatients (23 men, 50 women) aged 43.1 + 1.66 years (range, 16-66 years] with IBS symptoms lasting for more than 1 year. The patients were compared with 87 age- and sex-matched control subjects (25 men, 62 women] aged 37.9 * 0.9 years (range, 17-54 years). All patients had received diagnoses of IBS based on clinical criteria, and organic gastrointestinal disease had been excluded on previous occasions. Each patient had undergone at least a complete physical examination; full blood count; erythrocyte sedimentation rate (ESR); liver function tests; stool analysis for parasites, ova, and blood; and a sigmoidoscopy. Patients were recruited for this study only if they had diagnostic scores >44 points according to the criteria defined by Kruis et al. (14). Before the present investigation, complete histories and physical examinations were repeated, and laboratory examinations and sigmoidoscopy were repeated if more than 12 months had elapsed since the original examinations. The patients were assigned scores according to their main symptoms: pain-predominant, 41; constipation-predominant. 13; bloating-predominant, 12; and diarrhea-predominant. 7. Control subjects were selected from the hospital staff. None of the control subjects had abdominal symptoms, had been investigated for gastrointestinal diseases in the past, or had a history of serious illness. All control subjects had normal and regular bowel habits. Reasons for exclusion in both patients and controls included previous abdominal operations; previous organic gastrointestinal disease; disturbance of cardiorespiratory, hepatic, renal, or endocrinologic function; and the use of antibiotics or any other drug in the previous month. None of the patients or control subjects had a history of specific food intolerance or food allergy. Patients and control subjects were examined after an overnight fast of at least 10 hours. During the whole test period, all subjects continued fasting and refrained from smoking. All subjects were asked whether they had symptoms during the test. Fructose-sorbitol malabsorption was investigated by breath hydrogen testing in end-respiratory air samples that were collected in a 50-mL plastic syringe (15). After obtaining two basal samples at a &minute interval, the arithmetic mean was considered to be the basal H, excretion. Directly after obtaining the basal samples, an oral load of 25 g fructose and 5 g sorbitol dissolved in 150 mL tap water was given orally within 1 minute. This dose was chosen in analogy to previous studies (10~1~3). Breath samples were taken at 30-minute intervals for 3 hours and immediately analyzed. In these samples, hydrogen was analyzed by HZ-sensitive conductance using a Lactoscreen H, breath tester manufactured by Hoek Loos (Schiedam, The Netherlands) which has a range of o-200 ppm and an accuracy of *2%. Previously this method has been shown to have an excellent correlation with the gaschromatographic method (16). An increase of 20 ppm over basal values was regarded as evidence of FSM (9). The peak value of H, excretion above basal excretion (H,,,,) in ppm, the time to reach peak values (tH,,. in minutes, and the area under the curve of H, excretion above basal values (AU&,) in ppm - min were determined
ROLE OF FSM IN IBS PATIENTS
1017
considering the IBS and control group as a whole and only considering subjects with Hhnax >lO ppm and >20 ppm, respectively. Patients and control subjects were regarded as constitutional non-H, producers if no H, was expired after both the test solution and subsequent testing with 50 g la&dose.
During the whole test period, symptoms of bowel cramps, diarrhea, and flatulence were scored in patients and control subjects with the following scoring system: 0, absent; 1, minor (temporarily interfering with activities]: 2, moderate (all activities to be discontinued); 3, severe (needs to lie down). The proportions of malabsorbers in the IBS and control groups and the presence of symptoms during the test in either group were compared using the x2 test and Fisher’s exact test. Comparisons of Hamax,tHZmax,and AU&, were made with the Wilcoxon rank-sum test at a confidence level of +5%. All results are expressed as mean f SEM. The study was conducted in accordance with the Declaration of Helsinki-Tokyo and approved by the local ethical committee. All subjects gave written informed consent to participate in the study.
Results Three of 73 IBS patients and 2 of 87 control subjects were constitutional non-H, producers and were disregarded for analysis, leaving 70 patients and 85 control subjects suitable for evaluation. The mean values and SEM of H, excretion at any interval are shown in Table 1. At a cutoff level of HPmax20 ppm over basal values, 22 of 70 patients (31.4%) and 35 of 85 controls (41.5%) had FSM (P > 0.05). Thirty-three (47.1%) IBS patients and 50 (59.4%) controls had H,, more than 10 ppm over basal values (P > 0.05) (Table 2). The HBmaxwas 15.2 f 2.3 ppm in IBS patients and 21.5 f 2.6 ppm in controls, and the tH,,, was 110.7 + 5.4 minutes in IBS patients and 107.1 f 5.9 minutes in controls (P > 0.05). For subjects excreting more than 20 ppm H, above basal values, the H,, was 37.4 + 4.0 ppm in IBS patients and 41.7 * 3.4 ppm in controls, and the tHzmaxwas 109.5 + 7.6 minutes and 93.0 3t 7.2 minutes, respectively. For subjects excreting more than 10 ppm over basal values, the HPmaxwas 28.6 -c 3.4 ppm in patients and 31.3 + 3.1 ppm in controls, and the
Table 1. Breath Hydrogen (ppm) at 0,30,60,9O,X?O,l50, and 180 Minutes After Fructose-Sorbitol Loading 0
Patients Mean
SEM Control subjects Mean
SEM
30
3.22 4.96 0.62 0.88
60
90
120
150
180
9.22 12.66 11.00 11.49 0.38 1.53 1.88 1.59 1.79 1.14
3.89 6.34 15.63 16.67 15.52 12.12 11.50 0.53 1.11 2.05 2.41 1.64 1.66 1.42
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GASTROENTEROLOGY
Malabsorption in Patients and Control Subjects at Cutoff Levels of HSmax 20 ppm and 10 ppm Above Basal Values
Table 2. Fructose-Sorbitol
Patients (n = 70)
No.Hmax> 20 ppm (%) No. %ax
> 10 ppm
Controls In = 851
22
35 41.5 50 59.4
31.4 33 47.1
(%)
tH Pmax was 112.9 + 6.7 minutes and 104.7 + 6.9 minutes, respectively. The AUC,, was 1310 + 219 ppm - min in IBS patients and 1812 - 255 ppm - min in control subjects. The AU&. was 3467 & 414 ppm . min in IBS patients and 3610 t 418 ppm - min in controls if only subjects excreting more than 20 ppm over basal values were considered, and the values were 2583 + 335 ppm - min in patients and 2709 + 331 ppm - min in controls considering subjects with peak values 10 ppm above basal values (Table 3). Male and female IBS patients were comparable as to the presence of FSM (7 of 23 vs. 25 of 471, Hlmax (12.9 * 3.3 vs. 16.6 & 3.0) and AUC,, (1224 + 392 vs. 1331 + 267). Thirty-one of 70 patients developed symptoms during the test period (mean symptom score, 1.34) while only 3 of 85 control subjects developed symptoms. This difference is statistically significant (P < 0.0001). Of the 31 patients with symptoms, 23 had mild, 5 had moderate, and 3 had severe symptoms. Symptoms consisted of predominantly cramps in 12, predominantly diarrhea or flatulence in 9, and both in 10. Cramps were accompanied by nausea in 8 patients. Two control subjects had minor bowel cramps and one had moderate diarrhea. The control subject who developed diarrhea had a very high Hsmaxof 133 ppm over basal values. Symptoms were present in 19 of 50 female and 12 of 23 male patients (P > 0.05). Fructose-sorbitol malabTable 3. Hzmax(ppm), tHzmax[min), and ALJCa2[ppm . min)
in Patients and Control Subjects H *max Patients All H *max> 10 ppm %l,X > 20 ppm
Symptomatic Asymptomatic Controls All HZmax > 10~~ H zmaxz 20 ppm
15.2 + 28.6 k 37.4 + 20.3 f 10.5 +
tH,,,x
AU%,
2.3 3.4 4.0 4.2 1.9
110.7 t 5.4 112.9 + 6.7 109.5 + 7.6
1310 2583 3467 1800 844
21.5 + 2.6 31.3 + 3.1 41.7 + 3.4
107.1 * 5.9 104.7 + 6.9 93.0 + 7.2
1812 + 255 1708 + 331 3610 + 418
NOTE. All values are mean r SEM.
+ + + + f
219 335 414 399 207
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sorption at the 20-ppm level was present in 12 of 31 patients with symptoms and in 7 of 38 patients without symptoms (P = 0.11). At the lo-ppm level, FSM was present in 16 of 31 and 13 of 38, respectively (P = 0.21). In patients with symptoms, the Hzmaxwas 20.3 f 4.2 ppm (95% confidence limits between - 26 and +66.8) and the AU&, was 1800 + 399 ppm - min (95% confidence limits between - 2537 and +6163); and in patients without symptoms, the Hlmax was lo.5 + 1.9 ppm (95% confidence limits between - 11.5 and +33.3) and the AUCu, was 844 + 207 ppm . min (95% confidence limits between - 1443 and +3249) (P > 0.05).
Discussion In this study, we have shown that FSM is not more frequent in IBS patients than in control subjects. Hitherto, this is the first investigation dealing with FSM in IBS patients compared with an age- and sex-matched control group. The etiology of the IBS remains unknown. Psychogenic factors (17-19), motor disturbances (2O-2l), and food intolerance (l2,22) have been implicated as causes, but the condition is probably multifactorial. Based on incidental reports (12) and the finding that FSM measured by the breath H, test is found in a proportion of IBS patients, Rumessen and GudmandHoyer suggested that FSM is a factor in the etiology of IBS or IBS-like symptoms (13). Using H, breath testing in studying carbohydrate absorption, a 2%ppm increase of breath H, excretion over basal values is generally accepted (9,23,24). However, some authors have suggested that a lo-ppm increase may already be indicative of FSM (13,251. Therefore, we evaluated our results at both 20-ppm and lo-ppm cutoff levels. At a conventional level of a ZO-ppm increase of H, production, 9 of 25 IBS patients in the study of Rumessen and Gudmand-Hoyer showed evidence of malabsorption: at the lower cutoff level of 10 ppm, 13 of 25 showed malabsorption. These 13 patients were investigated for sorbitol malabsorption, which was present in 4 of them after a 5-g sorbitol load. Twelve of the 13 patients had malabsorption for the combined administration of 25 g fructose and 5 g sorbitol, which represents 36% and 52% of the total group using the respective cutoff levels of a 20-ppm and lo-ppm increase. The 12 patients not showing malabsorption of 25 g fructose were excluded from further analysis (13). However, in previous studies, the same authors showed malabsorption of 25 g fructose in 50% and malabsorption of 5 g sorbitol in 60% of healthy controls (9,10), and their study of IBS patients did not contain a control group. Hyams showed malabsorption of 5 g sorbitol in 4 of 7 healthy subjects (26).
October 1996
In this controlled study, FSM was found in 22 of 70 (31.4%) IBS patients and in 35 of 85 (41.5%) age- and sex-matched control subjects using the conventional cutoff level of Hzmax20 ppm over basal values and in 33 of 70 (47.1%) IBS patients and 50 of 85 (59.4%) controls using the lower cutoff level of 10 ppm increase over basal values. These percentages are in the same range for both healthy volunteers and IBS patients as found in uncontrolled studies by the other authors (13,26). Therefore, in our study FSM was not more frequently observed among IBS patients than among controls at either cutoff level. Also if quantative parameters of FSM (Hamax,tHzmau, and AUC,,) were measured, we did not find differences between patient and control groups as a whole, or in the subgroups with FSM measured at 20-ppm and lo-ppm levels (Table 3). The most frequent clinical symptom in the IBS group was abdominal pain. Patients with diarrhea-predominance were a minority in our study group, but did not differ from the other clinical subgroups. In Rumessen’s study of 25 IBS patients, 2 were male and 23 were female. Our study group, with 23 male and 50 female subjects, is more in accordance with the sex ratio of 1:2-3 reported in the literature (27). We did not find FSM to be more frequent in male or female subjects in either the patient group or the controls. In the IBS group, significantly more subjects developed symptoms during fructose-sorbitol loading than in the controlgroup (P < 0.0001). Because the presence or absence of FSM, Hgmax,or AUC,, did not significantly differ in asymptomatic patients, symptomatic patients, and control subjects, the development of symptoms is not readily explained by measurable differences in intestinal fructose-sorbitol handling. In patients developing symptoms during the test, fructosesorbitol probably constitutes an atypical stimulus to an irritated bowel system. It has been shown previously that IBS patients develop symptoms during balloon inflation of the colon at lower thresholds than control subjects (28) and are more prone to react to a variety of somatic stimuli (29,301. This probably reflects Read’s hypothesis of the hypersensitive gut (31) and is no evidence of an abnormality in fructose-sorbitol absorption. Therefore, we conclude that FSM does not play a role in the etiology of the IBS.
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ETIOLOGICAL ROLE OF FSM IN IBS PATIENTS
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4. Goldberg LD, Ditchek NT. Chewing gum diarrhea. Am J Dig Dis 1978;23:568. 5. Pochaczevsky R. Oral examination of the colon: “the colonic cocktail.” Am J Roentgen01 1974;121:318-325. 6. Levinsky NG, Alexander EA. Acute renal failure. In: Brenner BM, Rector FC, eds. The Kidney. Volume 2. Philadelphia: Saunders, 1976:806-837. 7. Crane RK. The physiology of the intestinal absorption of sugars. In: Jeannes A, Hodges J, eds. Physiological effects of food carbohydrates. Washington: American Chemical Society, 1975: 2-19. 8. Groen J. The absorption of hexoses from the upper part of the small intestine in man. J Clin Invest 1937:16:245-255. 9. Ravich WJ, Bayless TM, Thomas M. Fructose: incomplete intestinal absorption in humans. Gastroenterology 1983:84:2629. 10.Rumessen JJ, Gudmand-Hoyer E. Absorption capacity of fructose in healthy subjects. Comparison with sucrose and its constituent monosaccharides. Gut 1986;27:1161-1168. 11. Rumessen JJ, Gudmand-Hoyer E. Malabsorption of fructosesorbitol mixtures; interactions causing abdominal distress. Stand J Gastroenterol1987;22:431-436. 12.Andersson DEH, Nygren A. Four cases of long-standing diarrhoea and colic pains cured by fructose-free diet. A pathogenetic discussion. Acta Med Stand 1978;203:87-92. 13.Rumessen JJ, Gudmand-Hoyer E. Functional bowel disease: malabsorption and abdominal distress after ingestion of fructose, sorbitol and fructose-sorbitol mixtures. Gastroenterology 1988:95:694-700. 14.Kruis W, Thieme G. Weinzierl M, Schussler P, Ho01 J. Paulus W. A diagnostic score for the irritable bowel syndrome. Its value in exclusion of organic disease. Gastroenterology 1984;87:1-7. 15.Metz G. A simple method of measuring breath hydrogen in carbohydrate malabsorption by end expiratory sampling. Clin Sci Med 1976;50:237-240. 16.Douwes AC, Fernandes J. Degenhart HJ. Improved accuracy of lactose tolerancy test in children using expired H, measurements. Arch Dis Child 1978;53:939-942. 17. Almy T, Hinkle L, Burke B, Kern F. Alterations in colonic function in men under stress. Gastroenterology 1949;12:437-449. 18.Waller SL, Misiewicz JJ. Prognosis in irritable bowel syndrome. Lancet 1969;2:753-756. 19. Ealer MD, Goulston KJ. Levels of anxiety in colonic disorders. N EnglJ Med 1973;288:16-20. 20.Schuster MM, Whitehead WE. Physiologic insights into irritable bowel syndrome. Ballieres Clin Gastroenterol 1986;15:839-853. 21. Drossman DA, Lowman BC. Irritable bowel syndrome: epidemiology, diagnosis and treatment. Baillieres Clin Gastroenterol 1985;14:559-573. 22. Alun Jones V, Shorthouse M, McLaughlan P, Workman E. Hunter JO. Food intolerance: a major factor in the pathogenesis of irritable bowel syndrome. Lancet 1982;2:1115-1117. 23. Metz G, Jenkins DJ, Peters TJ. Breath hydrogen as a diagnostic method for hypolactasia. Lancet 1975;1:1155-1157. 24. Roman0 TJ, Dobbins JW. Evaluation of the patient with suspected malabsorption. Gastroenterol Clin North Am 1989;18:467484. 25.Barr RG, Watkins JB, Perman JA. Mucosal function and breath hydrogen excretion: comparative studies in the clinical evaluation of children with nonspecific abdominal complaints. Pediatrics 1981:68:526-533. 26.Hyams JS. Sorbitol intolerance: an unappreciated cause of functional gastrointestinal complaints. Gastroenterology 1983;84: 30-33. 27.Grant Thompson W. The irritable bowel. Gut 1984;25:305-320.
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28. Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the irritable bowel syndrome. Gut 1973;14:125-132. 29. Whitehead WE, Engel BT, Schuster MM. Irritable bowel syndrome. Physiological and psychological differences between diarrhea-predominant and constipation-predominant patients. Dig Dis Sci 1980;25:404-413. 30. Fielding JF. Clinical spectrum of the irritable bowel syndrome. Baillieres Clin Gastroenterol1977;6:607-622.
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31.Read NW. Irritable bowel syndrome (IBS)-definition and pathophysiology. Stand J Gastroenterol1987;13O(Suppl):7-13.
Received December 21,1989. Accepted April 16,199O. Address requests for reprints to: G. F. Nelis. M.D., Ph.D., Sophia Ziekenhuis PO 10400,800O GK Zwolle, The Netherlands.