Transient Lactose Malabsorption in Patients Affected by Symptomatic Uncomplicated Diverticular Disease of the Colon

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1 Digestive Diseases and Sciences, Vol. 51, No. 3 (March 2006), pp ( C 2006) DOI: /s Transient Lactose Malabsorption in Patients Affected by Symptomatic Uncomplicated Diverticular Disease of the Colon ANTONIO TURSI, MD,* GIOVANNI BRANDIMARTE, MD, GIAN MARCO GIORGETTI, MD, and WALTER ELISEI, MD Lactose malabsorption (LM) may be secondary to several small bowel diseases, and small intestinal overgrowth (SIBO) may be one of them. We looked for a correlation between symptomatic diverticular disease of the colon and LM and assessed whether this correlation may be related to SIBO. Ninety consecutive patients (pts; 39 males, 51 females; mean age, 67.2 years; range, years) affected by symptomatic uncomplicated diverticular disease of the colon were evaluated to assess orocecal transit time (OCTT), SIBO, and LM by lactulose and lactose H 2 breath test (H 2 -BT) at entry and after 8 weeks of treatment. OCTT was delayed in 67 of 90 pts (74.44%). Fifty-three of 90 pts (58.88%) showed SIBO, and OCTT was normal in 23 of 90 pts (25.56%). LM was diagnosed in 59 of 90 pts (65.55%): 49 of 59 (71.74%) were simultaneously affected by SIBO and delayed OCTT (and thus 49 of 53 pts [92.45%] with delayed OCTT and SIBO were affected by LM); 3 of 59 pts (5.09%) showed only delayed OCTT; 7 of 59 pts (11.86%) did not show either SIBO or delayed OCTT. The association of LM and SIBO was statistically significant (P < 0.001). Seventy-nine of 86 pts (91.86%) showed normal OCTT, while OCTT remained prolonged but shorter in the remaining 7 pts (8.14%). SIBO was eradicated in all pts completing the study, while a new lactulose H 2 -BT showed persistence of SIBO in one pt with recurrence of symptomatic diverticular disease. Forty-seven of 59 pts (79.66%) had a normal lactose H 2 -BT (P < 0.002), while 12 of 59 pts (20.34%) showed persistence of LM. LM disappeared in 46 of 49 pts (93.88%) concurrently with normalization of OCTT and eradication of SIBO (P < 0.002); it also disappeared in 1 of 3 pts (33.33%) previously affected by delayed OCTT (without SIBO) and LM concurrently with normalization of OCTT. On the contrary, it persisted in all pts with normal OCTT and absence of SIBO. Moreover, it persisted also in the pt with recurrence of symptomatic diverticular disease and persistence of SIBO. In conclusion, most pts affected by symptomatic uncomplicated diverticular disease of the colon showed LM, and in more than 70% of cases it disappeared after successful treatment of the colonic disease. KEY WORDS: diverticular disease of the colon; lactose malabsorption; small bowel bacterial overgrowth; orocecal transit time; treatment. Human hypolactasia is responsible for lactose malabsorption, which may cause symptoms such as abdominal pain, Manuscript received February 15, 2005; accepted June 15, From the *Digestive Endoscopy Unit, Lorenzo Bonomo Hospital, Andria (BA), Department of Internal Medicine, Division of Gastroenterology, Cristo Re Hospital, Rome, and Clinical Nutrition Unit, S. Eugenio Hospital, Rome, Italy. Address for reprint requests: Dr. Antonio Tursi, Galleria Pisani 4, Andria (BA), Italy; antotursi@tiscali.it. bloating, flatulence, and diarrhea, evoked by milk consumption (1). Primary lactose malabsorption is due to a genetically determined decline of lactase activity inherited through an autosomal recessive gene (2); however, lactose malabsorption may be secondary to several other small bowel diseases, such as celiac disease and Crohn s disease (3, 4). In these diseases orocecal transit time (OCTT) is delayed and it may influence the Digestive Diseases and Sciences, Vol. 51, No. 3 (March 2006) /06/ /0 C 2006 Springer Science+Business Media, Inc.

2 TURSI ET AL. clinical outcome of the disease (5 8), lactose intolerance included. Symptomatic uncomplicated diverticular disease of the colon is affected by some symptoms such as bloating, abdominal pain, flatulence, and diarrhea (9), similar to those of lactose malabsorption (10). Acute colonic diverticulitis is affected by bacterial colonic (11) and small intestinal (12) overgrowth (SIBO), which may contribute to the appearance of several gastrointestinal nonspecific symptoms (related to colonic and small bowel abnormalities). The aim of this study was to assess, first, whether there was a correlation between symptomatic uncomplicated diverticular disease of the colon and lactose malabsorption, second, whether this correlation may be related to SIBO, and third, whether lactose malabsorption had an influence on the clinical course of the colonic disease. MATERIALS AND METHODS A prospective study was conducted on 90 consecutive patients (39 males, 51 females; mean age, 67.2 years; range, years) affected by symptomatic uncomplicated diverticular disease of the colon, to assess OCTT and SIBO and lactose malabsorption. Diagnosis of symptomatic diverticular disease, defined as inflammation and/or infection associated with diverticula of the colon (13), was performed clinically and confirmed by colonoscopy. We assessed the following symptoms in all enrolled patients: (1) constipation, (2) diarrhea, (3) abdominal pain, (4) rectal bleeding, and (5) mucus passage with stools. The intensity of the symptoms was quantified using a quantitative scale (0 10 according to worsening of symptoms): 0, absence of symptoms; 1 2, slight symptoms; 3 5, mild symptoms; 6 7, moderate symptoms; and 8 10, severe symptoms. In order to avoid prolonged intestinal gas production, due to the presence of nonabsorbable or slowly fermentable material in the colonic lumen, the breath test (BT) was preceded by a preparation procedure based on the consumption, the evening before the test day, of a meal consisting of only rice, meat, and olive oil (14). This meal was followed by a 12-hr fasting period. Breath testing started between 0830 and 0930, after thorough mouth-washing with 40 ml of 1% chlorhexidine solution (15). Smoking (16) and physical exercise (17) were not allowed for 1 hr prior to and throughout the test. All subjects were studied after an overnight fast, having been instructed to avoid foods likely to generate hydrogen for the 24 hr before the test and to consume a meal of rice and meal; they were requested not to smoke on the morning of the test. In both tests, hydrogen concentrations in each collected sample were measured with a breath-hydrogen analyzer (EC60 Gastrolyzer Breath Hydrogen Monitor, Bedfont Scientific Ltd., Upchurch, Kent, UK). In order to assess the prevalence of SIBO, end expiratory samples were collected before the patients drank the test solution (10 g of lactulose suspended in 100 ml of tap water) and at 10-min intervals thereafter, for up to 240 min. OCTT was defined as the time elapsing between lactulose ingestion and a sustained increase in H 2 excretion of 10 ppm above the baseline value, which is about 75 ± 15 min (18). We also evaluated the presence of bacterial overgrowth, which was defined by the presence of a peak >20 ppm occurring >15 min before the colonic peak; also, patients with an elevated fasting H 2 combined with an early increase in H 2 after lactulose ingestion were considered positive for bacterial overgrowth (19). In order to assess lactose malabsorption, all patients were evaluated 3 days later by a lactose H 2 -BT. End expiratory samples were collected before the patients drank the test solution (20 g of lactose in 150 ml of tap water) and every 30 min for 4 hr. An increase in H 2 concentration of at least 20 ppm over fasting baseline was considered positive for lactose malabsorption. The cutoff for calculating the validity of the test was shifted every 30 min, and a response operating characteristics (ROC) curve (20) was plotted on the basis of the obtained results. All patients were treated with rifaximin (Rifacol; Formenti S.p.A, Milano, Italy), 800 mg/day, plus mesalazine (Pentacol 800; Sofar S.p.A., Trezzano Rosa [MI], Italy), 2.4 g/day, for 10 days, followed by mesalazine, 1.6 g/day, for 8 weeks. A medical control visit and new lactulose and lactose H 2 - BT were performed at the end of the eighth week of treatment with mesalazine alone. Moreover, the patients were invited to a control visit whenever they considered it necessary. We performed both per-protocol and intention-to-treat analyses. The intention-to-treat analysis included all patients recruited for this study, and all protocol violators were excluded from the per-protocol analysis. Moreover, 95% confidence intervals were provided. Statistical analysis was performed by χ 2 test. Statistical significance was achieved at P < RESULTS Diverticula were localized throughout the overall colon in 10 patients (11.11%), transverse-descending colonsigma in 13 patients (14.45%), left-sided colon in 12 patients (13.33%), descending colon-sigma in 45 cases (50%), sigma-rectum in 7 cases (7.78%), and rectum in 3 patients (3.33%). Sixty-one patients (67.78%) and 29 patients (32.22%) were affected by constipationand diarrhea-prevalent symptomatic diverticular disease, respectively. OCTT was delayed in 67 of 90 patients (74.44%), ranging from 115 to 210 min, with a mean of 120 min (see Figure 1). Fifty-three of 90 patients (58.88%) showed bacterial overgrowth, while OCTT was normal in 23 of 90 patients (25.56%), ranging from 75 to 90 min, with a mean of 82.5 min. When we subdivided the studied population according to bowel movements (constipation- or diarrhea-prevalent colonic symptomatic diverticular disease), we noted that OCTT was more prolonged in constipation-prevalent disease rather than diarrhea-prevalent disease: OCTT was min (range, min) and 121 min (range, min) in constipation- and diarrhea-prevalent symptomatic diverticular disease, respectively, with a 462 Digestive Diseases and Sciences, Vol. 51, No. 3 (March 2006)

3 LACTOSE MALABSORPTION IN DIVERTICULAR DISEASE OF COLON Fig 1. Lactose malabsorption in patients affected by symptomatic diverticular disease of the colon before and after treatment, and its relation to OCTT and SIBO (number of patients). See text for further information. statistically significant difference ( P < 0.001). Interestingly, we did not find any difference in bacterial overgrowth between these subgroups. In fact 26 of 53 (49.05%) and 27 of 53 (50.95%) of patients with SIBO were affected by constipation-prevalent and diarrhea-prevalent symptomatic diverticular disease (P = n.s.). Lactose malabsorption was diagnosed in 59 of 90 patients (65.55%): 49 of 59 (71.74%) were simultaneously affected by SIBO and delayed OCTT (and then 49 of 53 patients [92.45%] with delayed OCTT and SIBO were affected by lactose malabsorption); 3 of 59 (5.09%) showed only delayed OCTT; and 7 of 59 (11.86%) did not show either SIBO or delayed OCTT. The association of lactose malabsorption and SIBO shows statistical significance (P < 0.001). Seventy patients (per protocol, 81.49% [CI, 67 94%]; intention to treat, 77.78% [CI, 60 85%]) were completely asymptomatic after the eighth week of treatment with mesalazine alone (overall symptomatic score: 0), while 16 patients (per protocol, 18.60%; intention to treat, 17.77%) showed only slight symptoms (overall symptomatic score: 44). Two patients (2.22%) showed recurrence of symptomatic diverticular disease (abdominal pain, constipation, and fever) after 4 and 6 weeks of treatment with mesalazine alone, and two other patients (2.22%) showed severe side effects (severe diarrhea [more than 8 bowel movements/day]) and were withdrawn from the study. The overall score of patients decreased from 1439 to 44 (P < 0.001). Lactulose H 2 -BT was reevaluated at the end of the eighth week of treatment with mesalazine alone. Seventynine of 86 (91.86%) patients showed a normal OCTT, ranging from 75 to 105 min, with a mean of 83, while OCTT remained prolonged but shorter in the remaining 7 patients (8.14%), ranging from 105 to 115 min, with a mean of 110 min. SIBO was eradicated in all patients completing the study; on the contrary, a new lactulose H 2 -BT showed persistence of SIBO in one patient with recurrence of symptomatic diverticular disease. Three days later lactulose H 2 -BT and, also, lactose H 2 -BT were reevaluated (see Figure 1). Forty-seven of 59 patients (79.66%) had a normal lactose H 2 -BT (P < 0.002), while 12 of 59 (20.34%) showed persistence of lactose malabsorption. Looking at different subgroups affected by lactose malabsorption, we noted that lactose malabsorption disappeared in 46 of 49 (93.88%) patients previously affected by SIBO, delayed OCTT, and lactose malabsorption, concurrently with normalization of OCTT and eradication of SIBO ( P < 0.002). Lactose malabsorption disappeared in one of three (33.33%) patients previously affected by delayed OCTT (without SIBO) and lactose malabsorption concurrently with normalization of OCTT. On the contrary, lactose malabsorption persisted in all patients with a normal OCTT and absence of SIBO. Moreover, lactose malabsorption also persisted in the patient with recurrence of diverticular disease and persistence of SIBO. The relation among SIBO, OCTT, and lactose malabsorption before and after therapy is described in Figure 1. DISCUSSION Lactose malabsorption may induce clinical symptoms and shows a high prevalence in clinical practice. In most cases it is related to primary lactase deficiency, but in several other cases it is related to factors affecting the small Digestive Diseases and Sciences, Vol. 51, No. 3 (March 2006) 463

4 TURSI ET AL. bowel, with consequent decreasing in lactose absorption (21). This is the first study showing a high prevalence of lactose malabsorption in patients affected by symptomatic uncomplicated diverticular disease of the colon. Moreover, this study shows clearly that lactose malabsorption is strictly related to SIBO in these patients and that it may disappear after treatment of the symptomatic diverticular disease. But why does diverticulitis of the colon show lactose malabsorption? We can hypothesize a three-step process. The first step could be fecal stasis. In fact the muscle thickening observed in affected bowel segments was thought to be obstructive and to contribute to the delayed transit of feces (22). Studies with intracolonic displacement tools suggested that an accentuation of segmentary motor activity (as observed in diverticular disease) might abolish oro-aboral progression of contents (23), thereby facilitating retropulsion and drying of the semiliquid fecal matter. This first step leads to the second step: the appearance of SIBO, which could be related to colonic bacterial overgrowth. Changes in intestinal microflora may be one of the putative mechanisms responsible for colonic inflammation and could be the key point in the development of symptoms in acute uncomplicated diverticulitis. Acute diverticulitis is a condition characterized by abnormal colonic bacterial overgrowth (11): the latter condition, associated with the reverse peristalsis affecting the colon in diverticular disease, may thus favor small bowel colonization by colonic bacterial flora, provoking the SIBO. This hypothesis is confirmed by this study: most patients affected by acute diverticulitis of the colon showed a delayed OCTT (74.44%) and SIBO (58.88%). The appearance of SIBO leads to the third step in this process: the appearance of lactose malabsorption. The enzyme lactase is located on the intestinal brush border: it may be deranged by several diseases involving small bowel mucosa, such as small bowel infections. SIBO is characterized by an abnormal small bowel bacterial concentration (>8 billion/ml) (24), and in case of SIBO arising from colonic bacterial overgrowth, it can be characterized by aggressive colonic bacteria (such as Coliforms, Bacillus fragilis, and Clostrides): These bacteria may derange small bowel metabolic/enzymatic activity (and thus also lactase activity) and thus may provoke lactose malabsorption. We used lactulose instead of glucose to investigate SIBO in this study. This choice is related to the characteristics of the studied population. Since it is hypothesized that SIBO in these patients is related to small bowel migration of colonic flora, there is the risk that an easily adsorbable sugar such as glucose can be rapidly removed from the intestinal lumen and, thus, not available for bacterial fermentation in the distal small bowel. On the other hand, a poorly adsorbable sugar such as lactulose can be expected to be available for bacterial fermentation in cases of more distal small intestinal overgrowth (and acute diverticulitis may be one of these predisposing conditions): for these reasons we preferred to use lactulose instead of glucose. Why may lactose malabsorption be important in symptomatic uncomplicated diverticular disease of the colon in clinical practice? Because we think that it may worsen patients symptoms. Lactose malabsorption is characterized by nonspecific gastrointestinal complaints, such as bloating, abdominal pain, and flatulence. Unabsorbed lactose arrives quickly into the colon, provoking intraluminal sugar fermentation with production of great amounts of H 2 and CH 4 (causing bloating, abdominal pain, and flatulence) and an osmotic effect (with increasing bowel movements with diarrhea). These symptoms are indistinguishable from those of symptomatic uncomplicated diverticular disease, and patients affected by symptomatic diverticular disease of the colon may thus experience symptoms related to both pathological conditions. However, if lactose malabsorption is related to SIBO and thus to colonic diverticulitis, it is sufficient to treat the symptomatic diverticular disease to achieve disappearance of SIBO and thus restoration of lactase activity. The results obtained in this study confirm this hypothesis: in about 80% of patients affected by symptomatic diverticular disease, lactose malabsorption disappeared after treatment of colonic diverticulitis. Moreover, lactose malabsorption disappeared in more than 90% of patients previously affected by delayed OCTT, SIBO, and lactose malabsorption after treatment of colonic disease. CONCLUSIONS We conclude that most patients affected by acute symptomatic uncomplicated diverticular disease of the colon showed lactose malabsorption, and that in more that 70% of cases it disappeared after successful treatment of acute colonic disease. All of these patients should thus be investigated for lactose malabsorption, since the clinical picture of the colonic disease may benefit from transitory milk suspension. REFERENCES 1. Bayless TM, Rothfeld B, Massa C, Wise L, Paige D, Bedline MS: Lactose and milk intolerance: clinical implications. N Engl J Med 292: , Flatz G: Genetics of lactose digestion in humans. Adv Human Genet 16:1 77, Digestive Diseases and Sciences, Vol. 51, No. 3 (March 2006)

5 LACTOSE MALABSORPTION IN DIVERTICULAR DISEASE OF COLON 3. Bode S, Gudmand-Hoyer E: Incidence and clinical significance of lactose malabsorption in adult coeliac disease. Scand J Gastroenterol 32: , Mishkin B, Yalovsky M, Mishkin S: Increased prevalence of lactose malabsorption in Crohn s disease patients at low risk for lactose malabsorption based on ethnic origin. Am J Gastroenterol 92: , Tursi A: Clinical implications of delayed orocecal transit time and bacterial overgrowth in adult patients with Crohn s disease. J Clin Gastroenterol 32: , Chiarioni G, Bassotti G, Germani U, et al.: Gluten-free diet normalizes mouth-to-cecum transit of a caloric meal in adult patients with celiac disease. Dig Dis Sci 42: , Tursi A, Brandimarte G, Giorgetti GM, Nasi G: Assessment of orocecal transit time in different localisation of Crohn s disease and its possibile influence on clinical response to therapy. Eur J Gastroenterol Hepatol 15:69 74, Tursi A, Brandimarte G, Giorgetti GM: High prevalence of small intestinal bacterial overgrowth in celiac patients with persistence of gastrointestinal symptoms after gluten withdrawal. Am J Gastroenterol 98: , Tursi A: Acute diverticulitis of the colon Current medical therapeutic management. Expert Opin Pharmacother 5:55 59, intestinal bacterial overgrowth: response to antibiotic treatment. Age Ageing 20:29 32, Colecchia A, Sandri L, Capodicasa S, Vestito A, Mazzella G, Staniscia T, Roda E, Festi D: Diverticular disease of the colon: new perspectives in symptom development and treatment. World J Gastroenterol 9: , Tursi A, Brandimarte G, Giorgetti GM, Elisei W: Assessment of small intestinal bacterial overgowth in uncomplicated acute diverticulitis of the colon. World J Gastroenterol 11: , Stollman NH, Raskin JB: Diagnosis and management of diverticular disease of the colon. Am J Gastroenterol 94: , Kotler OP, Holt PR, Rosensweig NS: Modification of the breath test hydrogen test increased sensitivity fort he detection of carbohydrate malabsorption. J Lab Clin Med 100: , Thompson DG, O Brien JD, Hardie JM: Influence of the oropharyngeal microflora on the measurements of exhaled breath hydrogen. Gastroenterology 191: , Rosenthal A, Solomons NW: Time-course of cigarette smoke contamination of clinical hydrogen breath-analysis tests. Clin Chem 29: , Payne DL, Welsh JD, Claypool PL: Breath hydrogen (H2) response to carbohydrate malabsorption after exercise. J Lab Clin Med 102: , Hirikawa M, Iida M, Korogi N, Fujishima M: Hydrogen breath test assessment of oro-cecal transit time: comparison with barium meal study. Am J Gastroenterol 83: , Kerlin P, Wong L: Breath hydrogen testing in bacterial overgrowth of the small intestine. Gastroenterology 95: , Sackett DL, Haynes RB, Tugwell B: Clinical Epidemiology. A Basic Science for Clinical Medicine. Boston, Little, Brown, 1985, pp Tursi A: Factors influencing lactose intolerance. Eur J Clin Invest 34: , Raguse T, Bubenzer J: Functional and morphological studies on diverticulosis of the large bowel. Chir Forum Exp Klin Forsch , Garcia-Olmo D, Sanchez PC: Patterns of colonic motility as recorded by a sham fecaloma reveal differences among patients with idiopathic chronic constipation. Dis Colon Rectum 4: , Singh VV, Toskes PP: Small bowel bacterial overgrowth: presentation, diagnosis and treatment. Curr Treat Options Gastroenterol 7:19 28, 2004 Digestive Diseases and Sciences, Vol. 51, No. 3 (March 2006) 465

Original Article. Page 1 of 6

Original Article. Page 1 of 6 Original Article Page 1 of 6 Impact of diverticular inflammation and complication assessment classification on the burden of medical therapies in preventing diverticular disease complications in Italy