PRESENTATION
Small Intestinal Bacterial Overgrowth in Patients With Chronic Pancreatitis Marianna Signoretti, MD, Serena Stigliano, MD, Roberto Valente, MD, Matteo Piciucchi, MD, PhD, Gianfranco Delle Fave, MD, and Gabriele Capurso, MD, PhD
Goals: To assess the prevalence of small intestinal bacterial overgrowth (SIBO) in chronic pancreatitis (CP), and analyze factors related with SIBO in CP. Background: SIBO is to be considered a factor that worsens symptoms and nutritional status in patients with CP. However, the few studies evaluating the rate of SIBO in CP patients used nonuniform and nonstandardized procedures, and reported a wide range of positivity (0% to 92%). Those studies often investigated CP patients with previous resection surgery (cause of SIBO per se). Study: CP patients and controls evaluated for SIBO by the H2 glucose breath test with a standard protocol. For CP patients, the relationship between test results, abdominal symptoms, and clinical and biochemical variables was analyzed. Results: A total of 43 CP patients and 43 controls were enrolled. Of the CP patients, 8 had advanced disease (defined by M-ANNHEIM index) and none had undergone previous surgery. The glucose breath test positivity rate was higher in the CP patients than in the controls (21% vs. 14%), albeit without a significant difference (P = 0.57). Mean fasting H2 excretion and mean H2 excretion at 120 minutes also had a trend toward higher levels in CP patients. There were no clinical differences between CP patients with or without SIBO, but there were nutritional differences for lower levels of vitamin D and higher levels of folate in these patients with SIBO. Conclusions: Our findings suggest that SIBO is not uncommon in uncomplicated CP patients. The lack of a significant difference compared with controls might be due to the study being underpowered. SIBO in CP patients does not seem to be related to peculiar clinical features, but it might affect nutritional status. Key Words: bacterial overgrowth, chronic pancreatitis, pancreatic insufficiency, vitamin D
(J Clin Gastroenterol 2014;48:S52–S55)
T
he main symptom of chronic pancreatitis (CP) is abdominal pain, which might be associated with flatulence and weight loss due to exocrine pancreatic insufficiency (PEI). In patients with CP and PEI, fat maldigestion and malabsorption can ultimately result in steatorrhea and malnutrition.1 Pancreatic enzyme replacement therapy (PERT) is the therapy of choice to normalize digestion.2 However, gastrointestinal symptoms and nutritional status From the Digestive and Liver Disease Unit, S. Andrea Hospital, University “Sapienza,” Rome, Italy. The authors declare that they have nothing to disclose. Reprints: Gabriele Capurso, MD, PhD, Digestive and Liver Disease Unit, II Medical School, University “La Sapienza,” Ospedale S. Andrea, Via di Grottarossa 1035-1039 00189, Rome, Italy (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
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are not reversed by the use of adequate doses of pancreatic enzyme preparations in up to 50% of CP patients.3 In patients with insufficient response to PERT, the inhibition of gastric acid secretion with proton pump inhibitors (PPIs) should be attempted to improve the efficacy of therapy.3 Moreover, it has been suggested that the presence of small intestinal bacterial overgrowth (SIBO) should be considered in patients who do not respond to such treatments.2,4 SIBO is defined as an increase in the number and/or alteration in the type of bacteria in the upper gastrointestinal tract.5 The possible mechanisms leading to the development of SIBO in patients with CP have not been well clarified. Impaired small bowel motility, the lack of pancreatic juice proteolytic enzymes, which has an antibacterial effect, per se, an elevated alcohol intake, and the use of drugs such as PPIs and painkillers might all contribute to SIBO in CP. In patients with CP, the presence of SIBO could be clinically relevant, as a factor further worsening nutritional status. Indeed, the excess of bacteria can lead both to increased consumption of carbohydrates and of some vitamins and proteins, and to a decreased absorption of micronutrients due to the inactivation of pancreatic enzymes and to the bacterial deconjugation of bile salts.6 Finally, SIBO itself is associated with gastrointestinal symptoms including abdominal distension, increased flatus, abdominal pain, and diarrhea.5 Only a limited number of heterogenous studies have evaluated the rate of SIBO in small groups of CP patients.7–10 Moreover, those studies often investigated CP patients with previous resection surgery, which is considered a cause of SIBO per se. The primary aim of this study was therefore to assess the prevalence of SIBO in CP patients without a previous history of resection surgery. As a secondary aim, we aimed at evaluating the clinical and biochemical features related to SIBO in CP patients.
MATERIALS AND METHODS Patients and Controls The study population consisted of consecutive patients with CP attending the pancreatic disorders outpatients’ clinic. The inclusion criterion was a diagnosis of CP based on typical clinical and imaging features, and a functional test.11 Each patient underwent a detailed clinical evaluation to determine etiology and severity of CP, as well as assessment of symptoms throughout a standardized questionnaire. Exclusion criteria were a previous history of gastrointestinal surgery and/or concomitant diagnosis of other chronic gastrointestinal disorders such as inflammatory bowel disease or celiac disease. Controls were consecutive subjects with
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Volume 48, Supp. 1, November/December 2014
nonspecific, nonchronic gastrointestinal complaints seen at the outpatient’s clinic for the first time, and willing to participate in the study protocol. The local Ethics Committee approved the study protocol, and all patients and controls provided informed consent.
Glucose Hydrogen Breath Test (GBT) SIBO was diagnosed through GBT, performed using a portable breath gas analyzer (LactoFan, Fischer Analysen).12 The subjects were asked to follow a diet free of slowly absorbed carbohydrates and fibers on the day before the examination, to maintain low levels of fasting breath hydrogen excretion. The use of probiotics, antibiotics, and laxatives was not permitted over the 14 days prior the study. Cigarette smoking was not permitted on the day of and during the test. All subjects had to wash their mouth with a chlorhexidine solution before administration of the test substrate. The test protocol was the following: administration of glucose 50 g in 250 mL of water, samples of expired air collected every 20 minutes for direct measurement of H2 excretion over 120 minutes. The prevalence of SIBO was evaluated according with the criteria suggested by the Rome Consensus Conference.13 Therefore, an increase of hydrogen excretion over basal peak of Z12 parts per million (ppm) was considered as the cutoff value for the test positivity. A value for fasting breath hydrogen >20 ppm, despite adequate preparation, was also recorded as potentially suggesting test positivity.
SIBO in Patients With Chronic Pancreatitis
RESULTS Patient Characteristics Forty-three CP patients (55.8% male, mean age 54 y) and 43 healthy controls (48.8% male; mean age 47.4) were enrolled. Baseline characteristics of the 2 groups are detailed in Table 1. The controls were slightly younger when compared with the noncontrols. Seventeen of the 43 CP patients had an alcoholic etiology, 17 had pancreatic exocrine insufficiency, whereas 18 had an endocrine insufficiency, and 8 had advanced CP, defined using the M-ANNHEIM severity index.14
Results of Breath Analysis The GBT positivity rate, defined as a peak over basal of hydrogen excretion Z12 ppm, was higher in CP patients than in controls (6/43, 13.9% vs. 4/43, 9.3%), although this was not significant (P = 0.7). Taking into account values for basal breath hydrogen >20 ppm as a positive GBT, a further 3 CP patients and 2 controls had positive results. The overall positivity rate calculated, taking into account fasting values, reached 20.9% in CP patients versus 13.9% in healthy controls (P = 0.5) (Table 1). The mean fasting H2 breath hydrogen excretion was 6.91 ppm [95% confidence interval (CI): 3.7-10.1] in CP patients and 3.97 (95% CI: 1.8-6.1) in controls (P = 0.13), and the mean H2 breath hydrogen excretion at 120 minutes was 3.62 (95% CI: 2-5.3) in CP versus 2.31 (95% CI: 1.1-3.5) in controls (P = 0.19).
Association Between SIBO and Clinical and Biochemical Features in CP Patients
Nutritional Assessment All CP patients had their nutritional status investigated by assay of circulating levels of hemoglobin, vitamin D, calcium, vitamin B12, folate, total proteins, total cholesterol, and triglycerides. Patients and controls had their body weight and their height measured at the time of study inclusion. As regards CP patients, the relationship between GBT results, abdominal symptoms, and clinical and biochemical variables was analyzed.
Statistical Analysis Categorical data were compared by means of Fisher tests and continuous variables by means of t test for independent samples. A P < 0.05 was considered significant. A dedicated software (MedCalc, Mariakerke, Belgium) was used throughout the study.
Nine patients in the CP group had a diagnosis of SIBO. These 9 patients were slightly older than the 34 CP patients with a negative BT (61.6 vs. 52.05 y; P = 0.79). Patients with positive test results did not differ significantly from those with negative results in terms of CP etiology, severity of disease, time since initial CP diagnosis, prevalence of exocrine or endocrine insufficiency, treatment with PERT or PPIs, and the prevalence of symptoms (bloating, abdominal pain, and diarrhea) (see details in Table 2). As far as nutritional assessment is concerned, there were no differences between patients with and without SIBO, although there was a trend toward lower levels of vitamin D in CP patients with SIBO (15.9 vs. 25.16 ng/dL) (P = 0.08). In contrast, serum folate levels were slightly higher in CP patients with SIBO (16.5 vs. 8.32 ng/dL; P = 0.05).
TABLE 1. Baseline Characteristics of Included Patients and Frequency of SIBO Evaluated With H2 Peak Over Basal Excretion (HOB) and/ or Values of Basal Breath Hydrogen (H2 Basal) Age Sex (M:F) BMI HOBZ12 ppm (%) Fasting H2 > 20 ppm (%) HOBZ12 ppm or H2 basal >20 ppm (%) Mean fasting H2 excretion Mean H2 excretion at 120 min
Cases (n = 43)
Controls (n = 43)
P
54 (22-86) 24:19 23.35 (17.6-32.5) 13.9 7 20.9 6.91 ppm (95% CI: 3.7-10.1) 3.62 ppm (95% CI: 2-5.3)
47.4 (19-79) 21:22 23.76 (17.7-31.1) 9.3 4.7 13.9 3.97 ppm (95% CI: 1.8-6.1) 2.31 (95% CI: 1.1-3.5)
0.031 0.66 0.61 0.73 1 0.57 0.13 0.19
Age and BMI expressed as median (range), and HOB and H2 levels expressed as mean (95% confidence interval). BMI indicates body mass index; CI, confidence interval; H2, hydrogen; HOB, peak of hydrogen over basal; SIBO, small intestinal bacterial overgrowth.
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TABLE 2. Clinical and Biochemical Variables in Chronic Pancreatitis (CP) Patients With Positive (SIBO +) and Negative (SIBO –) Breath Test
SIBO + CP Patients (n = 9) Age Sex (M:F) Alcoholic etiology [n (%)] Time since diagnosis (mo) Advanced chronic pancreatitis [n (%)] BMI Pancreatic exocrine insufficiency [n (%)] Diabetes mellitus [n (%)] Pancreatic enzyme substitution therapy [n (%)] Proton pump inhibitor therapy [n (%)] Symptoms [n (%)]: Bloating Abdominal pain Diarrhea Laboratory tests Vitamin B12 (pg/mL) Hemoglobin (g/dL) Total proteins (g/dL) Vitamin D (ng/mL) Calcium (mg/dL) Serum folate (ng/mL) Total cholesterol (mg/dL) Triglycerides (mg/dL) Ferritin (ng/mL) Albumin (g/dL)
SIBO CP Patients (n = 34)
P
61.6 (39-86) 3:6 3 (33.3) 36.7 1 (11.1) 24.64 (17.7-32.5) 5 (55.5) 5 (55.5) 7 (77.7) 5 (55.5)
52 (22-76) 18:16 14 (41.17) 18 7 (20.6) 22.9 (17.6-30) 12 (35.3) 13 (38.2) 20 (58.8) 23 (67.6)
0.79 0.45 1 0.14 1 0.23 0.44 0.45 0.44 0.69
6 (66.6) 4 (44.4) 1 (11.1)
18 (52.9) 15 (44.1) 6 (17.6)
0.7 1 1
346 14.2 7 15.9 7.8 16.5 173.8 109.8 87.8 3.9
(95% (95% (95% (95% (95% (95% (95% (95% (95% (95%
CI: CI: CI: CI: CI: CI: CI: CI: CI: CI:
228.4-464.2) 13.2-15.2) 6.4-7.6) 11.2-20.8) 5.2-10.4) 9.9-33.9) 147-200.6) 61.7-157.9) 26.9-148.8) 3.5-4.4)
328 13.9 6.9 25.2 9 8.3 190.8 121.7 99.8 4.1
(95% (95% (95% (95% (95% (95% (95% (95% (95% (95%
CI: 194-462.3) CI: 13.2-14.5) CI: 6.7-7.2) CI:15.3 to 35) CI 8.4-9.6) CI: 5.1-11.5) CI: 172-209.7) CI: 94.8-148.7) CI: 62.8-136.9) CI: 3.8-4.4)
0.81 0.55 0.86 0.08 0.33 0.05 0.38 0.67 0.74 0.59
Age and BMI expressed as median (range), laboratory tests as mean (95% CI). BMI indicates body mass index; CI, confidence interval; SIBO, small intestinal bacterial overgrowth.
DISCUSSION The main finding of this study, conducted in the largest population examined with this aim, is that SIBO is a relatively common finding in CP patients without a previous history of surgery, being slightly more common than in healthy subjects (20.9% vs. 13.9%), although without a significant statistical difference between the 2 groups. In previous studies, the rate of SIBO in populations of CP patients was highly variable, ranging from 0% to 92%.7–10 Those studies were limited to cohorts of 11 to 35 patients, and had a high variability rate, justified by the use of nonstandardized BT protocols in terms of substrate, duration of the test, sampling intervals, and cutoff for the diagnosis of SIBO. In particular, Mancilla et al,7 who used a H2 lactulose breath test, a method that is prone to a high rate of false positivity,15,16 reported the highest positivity rate (92%). Moreover, some of those studies included CP patients with a previous history of gastroduodenal surgery,7–9 which is considered a cause of SIBO per se. In detail, Casellas et al9 reported a prevalence of SIBO of 40% in the CP group, but almost all CP patients (10/15) had gastroduodenal surgery, whereas 8 of 35 CP patients had a previous surgical treatment in the study of Trespi and Ferrieri,8 which reported a prevalence of SIBO equal to 35%. Interestingly, in the only other study10 that excluded patients with a previous history of surgery, the positivity rate in the CP group was 0%. However, that study was limited to 11 CP patients only, and the exact dose of glucose administrated was not clearly specified. Moreover, the selection of controls in some studies was also questionable, as, in 2 of those studies, CP patients were compared with patients affected either by primary immunodeficiency9 or with previous gastric resection,8 with both of these conditions being linked with alterations in intestinal microbiota.
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This study is the first to evaluate the prevalence of SIBO using a standardized GBT protocol, according to the criteria suggested by the Rome Consensus Conference,13 in a population of uncomplicated CP patients (without gastrointestinal surgery) to evaluate the actual rate of SIBO associated with CP as compared with a control population, without disorders specifically associated with SIBO. However, there are some limitations to this study. Firstly, although GBT is considered the most accurate noninvasive examination for the diagnosis of SIBO, its accuracy is only equal to 71.7%13 compared with jejunal aspiration and culture, which is considered the gold standard. However, because of the invasiveness of this method, which requires intubation of the small bowel, GBT must be considered the most accurate noninvasive test for diagnosis of SIBO in clinical practice. Furthermore, in this study, we did not evaluate the presence of methanogenic bacteria in the gut that might convert hydrogen into methane, and we cannot therefore rule out the presence of false-negative results because of the lack of measurement of both gases. Thirdly, the lack of a significant difference in the prevalence of SIBO as compared with controls in this study might suggest that the study was underpowered. Moreover, the 13.9% positivity rate observed in our control population seems slightly higher than the approximately 4% previously reported in healthy subjects.17 It is therefore possible that among the controls recruited for nonspecific gastrointestinal symptoms, there were subjects with irritable bowel syndrome, a condition that has previously been reported to be associated with SIBO, with a range of positivity around 30%.17,18 Therefore, we cannot exclude the possibility that the investigation of a larger cohort and the selection of a different control population might have led to a more significant difference between CP patients and controls. Nevertheless, the r
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finding that one fifth of patients with uncomplicated CP have SIBO might have important clinical consequences. The secondary aim of the study was to analyze the clinical and biochemical factors related to SIBO in CP patients. Our findings show a trend toward reduced vitamin D levels in CP patients with SIBO (15.9 vs. 25.16 ng/dL; P = 0.08). This result is biologically plausible, as deficiencies in fat-soluble vitamins, including vitamin D, because of fat malabsorption due to bacterial deconjugation of bile salts, and related metabolic bone diseases with osteopenia and osteomalacia, have been reported in patients with SIBO.19–21 As patients with CP might exhibit malabsorption of lipid soluble vitamins, such as vitamin D and vitamin K2, that are important for bone metabolism, and osteoporosis is frequent in CP patients,22 the possible relationship between SIBO, vitamin D levels, and bone density seems an interesting area for future research. Another interesting finding is represented by the higher serum folate levels observed in CP patient with SIBO (16.5 vs. 8.32 ng/dL; P = 0.054). This alteration has already been described in patients with SIBO,23 and is considered secondary to the bacterial fermentation of substrates present in the intestinal lumen, with the consequent increased production of folates. In conclusion, our findings suggest that SIBO is not uncommon in CP, even in a population of uncomplicated patients. SIBO in CP patients does not seem related to peculiar clinical features or medical treatment with PERT or PPIs, but it could affect nutritional status. Thus, it could be useful to exclude the presence of SIBO not only in CP patients with PEI unresponsive to pancreatic enzymes, as suggested by some authors,2,4 but in every CP patient. Further studies, conducted in larger populations of CP patients with different disease severity, are needed to better assess the clinical relevance of SIBO in CP. Finally, it will be important to evaluate the efficacy of a standardized treatment for SIBO, such as rifaximin, in the setting of CP, particularly regarding the possible subsequent improvement in nutritional status.
REFERENCES 1. Bruno MJ, Haverkort EB, Tytgat GN, et al. Maldigestion associated with exocrine pancreatic insufficiency: implications of gastrointestinal physiology and properties of enzyme preparations for a cause-related and patient-tailored treatment. Am J Gastroenterol. 1995;90:1383–1393. 2. Domı´ nguez-Mun˜oz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Curr Gastroenterol Rep. 2007;9:116–122. 3. Domı´ nguez-Mun˜oz JE, Iglesias-Garcı´ a J, Iglesias-Rey M, et al. Optimising the therapy of exocrine pancreatic insufficiency by the association of a proton pump inhibitor to enteric coated pancreatic extracts. Gut. 2006;55:1056–1057. 4. Toouli J, Biankin AV, Oliver MR, et al. Management of pancreatic exocrine insufficiency: Australasian Pancreatic Club recommendations. Med J Aust. 2010;193:461–467.
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5. Bures J, Cyrany J, Kohoutova D, et al. Small intestinal bacterial overgrowth syndrome. World J Gastroenterol. 2010; 16:2978–2990. 6. Gubergrits NB, Linevskiy YV, Lukashevich GM, et al. Morphological and functional alterations of small intestine in chronic pancreatitis. JOP. 2012;13:519–528. 7. Mancilla AC, Madrid SAM, Hurtado HC, et al. Small intestine bacterial overgrowth in patients with chronic pancreatitis. Rev Med Chil. 2008;136:976–980. 8. Trespi E, Ferrieri A. Intestinal bacterial overgrowth during chronic pancreatitis. Curr Med Res Opin. 1999;15:47–52. 9. Casellas F, Guarner L, Vaquero E, et al. Hydrogen breath test with glucose in exocrine pancreatic insufficiency. Pancreas. 1998;16:481–486. 10. Madsen JL, Graff J, Philipsen EK, et al. Bile acid malabsorption or disturbed intestinal permeability in patients treated with enzyme substitution for exocrine pancreatic insufficiency is not caused by bacterial overgrowth. Pancreas. 2003;26: 130–133. 11. Sarles H, Adler G, Dani R, et al. The pancreatitis classification of Marseilles-Rome 1988. Scand J Gastroenterol. 1989;24: 641–642. 12. Lee WS, Davidson GP, Moore DJ, et al. Analysis of the breath hydrogen test for carbohydrate malabsorption: validation of a pocket-sized breath test analyser. J Paediatr Child Health. 2000;36:340–342. 13. Gasbarrini A, Corazza GR, Gasbarrini G, et al. Methodology and indications of H2-breath testing in gastrointestinal diseases: the Rome Consensus Conference. Aliment Pharmacol Ther. 2009;29:1–49. 14. Schneider A, Lo¨hr JM, Singer MV. The M-ANNHEIM classification of chronic pancreatitis: introduction of a unifying classification system based on a review of previous classifications of the disease. J Gastroenterol. 2007;42:101–119. 15. Kerlin P, Wong L. Breath hydrogen testing in bacterial overgrowth of the small intestine. Gastroenterology. 1988; 95:982–988. 16. Corazza GR, Menozzi MG, Strocchi A, et al. The diagnosis of small bowel bacterial overgrowth. Reliability of jejunal culture and inadequacy of breath hydrogen testing. Gastroenterology. 1990;98:302–309. 17. Lupascu A, Gabrielli M, Lauritano EC, et al. Hydrogen glucose breath test to detect small intestinal bacterial overgrowth: a prevalence case-control study in irritable bowel syndrome. Aliment Pharmacol Ther. 2005;22:1157–1160. 18. Cuoco L, Salvagnini M. Small intestine bacterial overgrowth in irritable bowel syndrome: a retrospective study with rifaximin. Minerva Gastroenterol Dietol. 2006;52:89–95. 19. Stotzer PO, Johansson C, Mellstro¨m D, et al. Bone mineral density in patients with small intestinal bacterial overgrowth. Hepatogastroenterology. 2003;50:1415–1418. 20. Anantharaju A, Klamut M. Small intestinal bacterial overgrowth: a possible risk factor for metabolic bone disease. Nutr Rev. 2003;61:132–135. 21. Di Stefano M, Veneto G, Malservisi S, et al. Small intestine bacterial overgrowth and metabolic bone disease. Dig Dis Sci. 2001;46:1077–1082. 22. Duggan SN, Smyth ND, Murphy A, et al. High prevalence of osteoporosis in patients with chronic pancreatitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2014;12: 219–228. 23. Gracey M. Intestinal absorption in the “contaminated smallbowel syndrome”. Gut. 1971;12:403–410.
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Small Intestinal Bacterial Overgrowth in Patients With Chronic Pancreatitis Marianna Signoretti, MD, Serena Stigliano, MD, Roberto Valente, MD, Matteo Piciucchi, MD, PhD, Gianfranco Delle Fave, MD, and Gabriele Capurso, MD, PhD
Goals: To assess the prevalence of small intestinal bacterial overgrowth (SIBO) in chronic pancreatitis (CP), and analyze factors related with SIBO in CP. Background: SIBO is to be considered a factor that worsens symptoms and nutritional status in patients with CP. However, the few studies evaluating the rate of SIBO in CP patients used nonuniform and nonstandardized procedures, and reported a wide range of positivity (0% to 92%). Those studies often investigated CP patients with previous resection surgery (cause of SIBO per se). Study: CP patients and controls evaluated for SIBO by the H2 glucose breath test with a standard protocol. For CP patients, the relationship between test results, abdominal symptoms, and clinical and biochemical variables was analyzed. Results: A total of 43 CP patients and 43 controls were enrolled. Of the CP patients, 8 had advanced disease (defined by M-ANNHEIM index) and none had undergone previous surgery. The glucose breath test positivity rate was higher in the CP patients than in the controls (21% vs. 14%), albeit without a significant difference (P = 0.57). Mean fasting H2 excretion and mean H2 excretion at 120 minutes also had a trend toward higher levels in CP patients. There were no clinical differences between CP patients with or without SIBO, but there were nutritional differences for lower levels of vitamin D and higher levels of folate in these patients with SIBO. Conclusions: Our findings suggest that SIBO is not uncommon in uncomplicated CP patients. The lack of a significant difference compared with controls might be due to the study being underpowered. SIBO in CP patients does not seem to be related to peculiar clinical features, but it might affect nutritional status. Key Words: bacterial overgrowth, chronic pancreatitis, pancreatic insufficiency, vitamin D
(J Clin Gastroenterol 2014;48:S52–S55)
T
he main symptom of chronic pancreatitis (CP) is abdominal pain, which might be associated with flatulence and weight loss due to exocrine pancreatic insufficiency (PEI). In patients with CP and PEI, fat maldigestion and malabsorption can ultimately result in steatorrhea and malnutrition.1 Pancreatic enzyme replacement therapy (PERT) is the therapy of choice to normalize digestion.2 However, gastrointestinal symptoms and nutritional status From the Digestive and Liver Disease Unit, S. Andrea Hospital, University “Sapienza,” Rome, Italy. The authors declare that they have nothing to disclose. Reprints: Gabriele Capurso, MD, PhD, Digestive and Liver Disease Unit, II Medical School, University “La Sapienza,” Ospedale S. Andrea, Via di Grottarossa 1035-1039 00189, Rome, Italy (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
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are not reversed by the use of adequate doses of pancreatic enzyme preparations in up to 50% of CP patients.3 In patients with insufficient response to PERT, the inhibition of gastric acid secretion with proton pump inhibitors (PPIs) should be attempted to improve the efficacy of therapy.3 Moreover, it has been suggested that the presence of small intestinal bacterial overgrowth (SIBO) should be considered in patients who do not respond to such treatments.2,4 SIBO is defined as an increase in the number and/or alteration in the type of bacteria in the upper gastrointestinal tract.5 The possible mechanisms leading to the development of SIBO in patients with CP have not been well clarified. Impaired small bowel motility, the lack of pancreatic juice proteolytic enzymes, which has an antibacterial effect, per se, an elevated alcohol intake, and the use of drugs such as PPIs and painkillers might all contribute to SIBO in CP. In patients with CP, the presence of SIBO could be clinically relevant, as a factor further worsening nutritional status. Indeed, the excess of bacteria can lead both to increased consumption of carbohydrates and of some vitamins and proteins, and to a decreased absorption of micronutrients due to the inactivation of pancreatic enzymes and to the bacterial deconjugation of bile salts.6 Finally, SIBO itself is associated with gastrointestinal symptoms including abdominal distension, increased flatus, abdominal pain, and diarrhea.5 Only a limited number of heterogenous studies have evaluated the rate of SIBO in small groups of CP patients.7–10 Moreover, those studies often investigated CP patients with previous resection surgery, which is considered a cause of SIBO per se. The primary aim of this study was therefore to assess the prevalence of SIBO in CP patients without a previous history of resection surgery. As a secondary aim, we aimed at evaluating the clinical and biochemical features related to SIBO in CP patients.
MATERIALS AND METHODS Patients and Controls The study population consisted of consecutive patients with CP attending the pancreatic disorders outpatients’ clinic. The inclusion criterion was a diagnosis of CP based on typical clinical and imaging features, and a functional test.11 Each patient underwent a detailed clinical evaluation to determine etiology and severity of CP, as well as assessment of symptoms throughout a standardized questionnaire. Exclusion criteria were a previous history of gastrointestinal surgery and/or concomitant diagnosis of other chronic gastrointestinal disorders such as inflammatory bowel disease or celiac disease. Controls were consecutive subjects with
J Clin Gastroenterol
Volume 48, Supp. 1, November/December 2014
J Clin Gastroenterol
Volume 48, Supp. 1, November/December 2014
nonspecific, nonchronic gastrointestinal complaints seen at the outpatient’s clinic for the first time, and willing to participate in the study protocol. The local Ethics Committee approved the study protocol, and all patients and controls provided informed consent.
Glucose Hydrogen Breath Test (GBT) SIBO was diagnosed through GBT, performed using a portable breath gas analyzer (LactoFan, Fischer Analysen).12 The subjects were asked to follow a diet free of slowly absorbed carbohydrates and fibers on the day before the examination, to maintain low levels of fasting breath hydrogen excretion. The use of probiotics, antibiotics, and laxatives was not permitted over the 14 days prior the study. Cigarette smoking was not permitted on the day of and during the test. All subjects had to wash their mouth with a chlorhexidine solution before administration of the test substrate. The test protocol was the following: administration of glucose 50 g in 250 mL of water, samples of expired air collected every 20 minutes for direct measurement of H2 excretion over 120 minutes. The prevalence of SIBO was evaluated according with the criteria suggested by the Rome Consensus Conference.13 Therefore, an increase of hydrogen excretion over basal peak of Z12 parts per million (ppm) was considered as the cutoff value for the test positivity. A value for fasting breath hydrogen >20 ppm, despite adequate preparation, was also recorded as potentially suggesting test positivity.
SIBO in Patients With Chronic Pancreatitis
RESULTS Patient Characteristics Forty-three CP patients (55.8% male, mean age 54 y) and 43 healthy controls (48.8% male; mean age 47.4) were enrolled. Baseline characteristics of the 2 groups are detailed in Table 1. The controls were slightly younger when compared with the noncontrols. Seventeen of the 43 CP patients had an alcoholic etiology, 17 had pancreatic exocrine insufficiency, whereas 18 had an endocrine insufficiency, and 8 had advanced CP, defined using the M-ANNHEIM severity index.14
Results of Breath Analysis The GBT positivity rate, defined as a peak over basal of hydrogen excretion Z12 ppm, was higher in CP patients than in controls (6/43, 13.9% vs. 4/43, 9.3%), although this was not significant (P = 0.7). Taking into account values for basal breath hydrogen >20 ppm as a positive GBT, a further 3 CP patients and 2 controls had positive results. The overall positivity rate calculated, taking into account fasting values, reached 20.9% in CP patients versus 13.9% in healthy controls (P = 0.5) (Table 1). The mean fasting H2 breath hydrogen excretion was 6.91 ppm [95% confidence interval (CI): 3.7-10.1] in CP patients and 3.97 (95% CI: 1.8-6.1) in controls (P = 0.13), and the mean H2 breath hydrogen excretion at 120 minutes was 3.62 (95% CI: 2-5.3) in CP versus 2.31 (95% CI: 1.1-3.5) in controls (P = 0.19).
Association Between SIBO and Clinical and Biochemical Features in CP Patients
Nutritional Assessment All CP patients had their nutritional status investigated by assay of circulating levels of hemoglobin, vitamin D, calcium, vitamin B12, folate, total proteins, total cholesterol, and triglycerides. Patients and controls had their body weight and their height measured at the time of study inclusion. As regards CP patients, the relationship between GBT results, abdominal symptoms, and clinical and biochemical variables was analyzed.
Statistical Analysis Categorical data were compared by means of Fisher tests and continuous variables by means of t test for independent samples. A P < 0.05 was considered significant. A dedicated software (MedCalc, Mariakerke, Belgium) was used throughout the study.
Nine patients in the CP group had a diagnosis of SIBO. These 9 patients were slightly older than the 34 CP patients with a negative BT (61.6 vs. 52.05 y; P = 0.79). Patients with positive test results did not differ significantly from those with negative results in terms of CP etiology, severity of disease, time since initial CP diagnosis, prevalence of exocrine or endocrine insufficiency, treatment with PERT or PPIs, and the prevalence of symptoms (bloating, abdominal pain, and diarrhea) (see details in Table 2). As far as nutritional assessment is concerned, there were no differences between patients with and without SIBO, although there was a trend toward lower levels of vitamin D in CP patients with SIBO (15.9 vs. 25.16 ng/dL) (P = 0.08). In contrast, serum folate levels were slightly higher in CP patients with SIBO (16.5 vs. 8.32 ng/dL; P = 0.05).
TABLE 1. Baseline Characteristics of Included Patients and Frequency of SIBO Evaluated With H2 Peak Over Basal Excretion (HOB) and/ or Values of Basal Breath Hydrogen (H2 Basal) Age Sex (M:F) BMI HOBZ12 ppm (%) Fasting H2 > 20 ppm (%) HOBZ12 ppm or H2 basal >20 ppm (%) Mean fasting H2 excretion Mean H2 excretion at 120 min
Cases (n = 43)
Controls (n = 43)
P
54 (22-86) 24:19 23.35 (17.6-32.5) 13.9 7 20.9 6.91 ppm (95% CI: 3.7-10.1) 3.62 ppm (95% CI: 2-5.3)
47.4 (19-79) 21:22 23.76 (17.7-31.1) 9.3 4.7 13.9 3.97 ppm (95% CI: 1.8-6.1) 2.31 (95% CI: 1.1-3.5)
0.031 0.66 0.61 0.73 1 0.57 0.13 0.19
Age and BMI expressed as median (range), and HOB and H2 levels expressed as mean (95% confidence interval). BMI indicates body mass index; CI, confidence interval; H2, hydrogen; HOB, peak of hydrogen over basal; SIBO, small intestinal bacterial overgrowth.
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TABLE 2. Clinical and Biochemical Variables in Chronic Pancreatitis (CP) Patients With Positive (SIBO +) and Negative (SIBO –) Breath Test
SIBO + CP Patients (n = 9) Age Sex (M:F) Alcoholic etiology [n (%)] Time since diagnosis (mo) Advanced chronic pancreatitis [n (%)] BMI Pancreatic exocrine insufficiency [n (%)] Diabetes mellitus [n (%)] Pancreatic enzyme substitution therapy [n (%)] Proton pump inhibitor therapy [n (%)] Symptoms [n (%)]: Bloating Abdominal pain Diarrhea Laboratory tests Vitamin B12 (pg/mL) Hemoglobin (g/dL) Total proteins (g/dL) Vitamin D (ng/mL) Calcium (mg/dL) Serum folate (ng/mL) Total cholesterol (mg/dL) Triglycerides (mg/dL) Ferritin (ng/mL) Albumin (g/dL)
SIBO CP Patients (n = 34)
P
61.6 (39-86) 3:6 3 (33.3) 36.7 1 (11.1) 24.64 (17.7-32.5) 5 (55.5) 5 (55.5) 7 (77.7) 5 (55.5)
52 (22-76) 18:16 14 (41.17) 18 7 (20.6) 22.9 (17.6-30) 12 (35.3) 13 (38.2) 20 (58.8) 23 (67.6)
0.79 0.45 1 0.14 1 0.23 0.44 0.45 0.44 0.69
6 (66.6) 4 (44.4) 1 (11.1)
18 (52.9) 15 (44.1) 6 (17.6)
0.7 1 1
346 14.2 7 15.9 7.8 16.5 173.8 109.8 87.8 3.9
(95% (95% (95% (95% (95% (95% (95% (95% (95% (95%
CI: CI: CI: CI: CI: CI: CI: CI: CI: CI:
228.4-464.2) 13.2-15.2) 6.4-7.6) 11.2-20.8) 5.2-10.4) 9.9-33.9) 147-200.6) 61.7-157.9) 26.9-148.8) 3.5-4.4)
328 13.9 6.9 25.2 9 8.3 190.8 121.7 99.8 4.1
(95% (95% (95% (95% (95% (95% (95% (95% (95% (95%
CI: 194-462.3) CI: 13.2-14.5) CI: 6.7-7.2) CI:15.3 to 35) CI 8.4-9.6) CI: 5.1-11.5) CI: 172-209.7) CI: 94.8-148.7) CI: 62.8-136.9) CI: 3.8-4.4)
0.81 0.55 0.86 0.08 0.33 0.05 0.38 0.67 0.74 0.59
Age and BMI expressed as median (range), laboratory tests as mean (95% CI). BMI indicates body mass index; CI, confidence interval; SIBO, small intestinal bacterial overgrowth.
DISCUSSION The main finding of this study, conducted in the largest population examined with this aim, is that SIBO is a relatively common finding in CP patients without a previous history of surgery, being slightly more common than in healthy subjects (20.9% vs. 13.9%), although without a significant statistical difference between the 2 groups. In previous studies, the rate of SIBO in populations of CP patients was highly variable, ranging from 0% to 92%.7–10 Those studies were limited to cohorts of 11 to 35 patients, and had a high variability rate, justified by the use of nonstandardized BT protocols in terms of substrate, duration of the test, sampling intervals, and cutoff for the diagnosis of SIBO. In particular, Mancilla et al,7 who used a H2 lactulose breath test, a method that is prone to a high rate of false positivity,15,16 reported the highest positivity rate (92%). Moreover, some of those studies included CP patients with a previous history of gastroduodenal surgery,7–9 which is considered a cause of SIBO per se. In detail, Casellas et al9 reported a prevalence of SIBO of 40% in the CP group, but almost all CP patients (10/15) had gastroduodenal surgery, whereas 8 of 35 CP patients had a previous surgical treatment in the study of Trespi and Ferrieri,8 which reported a prevalence of SIBO equal to 35%. Interestingly, in the only other study10 that excluded patients with a previous history of surgery, the positivity rate in the CP group was 0%. However, that study was limited to 11 CP patients only, and the exact dose of glucose administrated was not clearly specified. Moreover, the selection of controls in some studies was also questionable, as, in 2 of those studies, CP patients were compared with patients affected either by primary immunodeficiency9 or with previous gastric resection,8 with both of these conditions being linked with alterations in intestinal microbiota.
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This study is the first to evaluate the prevalence of SIBO using a standardized GBT protocol, according to the criteria suggested by the Rome Consensus Conference,13 in a population of uncomplicated CP patients (without gastrointestinal surgery) to evaluate the actual rate of SIBO associated with CP as compared with a control population, without disorders specifically associated with SIBO. However, there are some limitations to this study. Firstly, although GBT is considered the most accurate noninvasive examination for the diagnosis of SIBO, its accuracy is only equal to 71.7%13 compared with jejunal aspiration and culture, which is considered the gold standard. However, because of the invasiveness of this method, which requires intubation of the small bowel, GBT must be considered the most accurate noninvasive test for diagnosis of SIBO in clinical practice. Furthermore, in this study, we did not evaluate the presence of methanogenic bacteria in the gut that might convert hydrogen into methane, and we cannot therefore rule out the presence of false-negative results because of the lack of measurement of both gases. Thirdly, the lack of a significant difference in the prevalence of SIBO as compared with controls in this study might suggest that the study was underpowered. Moreover, the 13.9% positivity rate observed in our control population seems slightly higher than the approximately 4% previously reported in healthy subjects.17 It is therefore possible that among the controls recruited for nonspecific gastrointestinal symptoms, there were subjects with irritable bowel syndrome, a condition that has previously been reported to be associated with SIBO, with a range of positivity around 30%.17,18 Therefore, we cannot exclude the possibility that the investigation of a larger cohort and the selection of a different control population might have led to a more significant difference between CP patients and controls. Nevertheless, the r
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finding that one fifth of patients with uncomplicated CP have SIBO might have important clinical consequences. The secondary aim of the study was to analyze the clinical and biochemical factors related to SIBO in CP patients. Our findings show a trend toward reduced vitamin D levels in CP patients with SIBO (15.9 vs. 25.16 ng/dL; P = 0.08). This result is biologically plausible, as deficiencies in fat-soluble vitamins, including vitamin D, because of fat malabsorption due to bacterial deconjugation of bile salts, and related metabolic bone diseases with osteopenia and osteomalacia, have been reported in patients with SIBO.19–21 As patients with CP might exhibit malabsorption of lipid soluble vitamins, such as vitamin D and vitamin K2, that are important for bone metabolism, and osteoporosis is frequent in CP patients,22 the possible relationship between SIBO, vitamin D levels, and bone density seems an interesting area for future research. Another interesting finding is represented by the higher serum folate levels observed in CP patient with SIBO (16.5 vs. 8.32 ng/dL; P = 0.054). This alteration has already been described in patients with SIBO,23 and is considered secondary to the bacterial fermentation of substrates present in the intestinal lumen, with the consequent increased production of folates. In conclusion, our findings suggest that SIBO is not uncommon in CP, even in a population of uncomplicated patients. SIBO in CP patients does not seem related to peculiar clinical features or medical treatment with PERT or PPIs, but it could affect nutritional status. Thus, it could be useful to exclude the presence of SIBO not only in CP patients with PEI unresponsive to pancreatic enzymes, as suggested by some authors,2,4 but in every CP patient. Further studies, conducted in larger populations of CP patients with different disease severity, are needed to better assess the clinical relevance of SIBO in CP. Finally, it will be important to evaluate the efficacy of a standardized treatment for SIBO, such as rifaximin, in the setting of CP, particularly regarding the possible subsequent improvement in nutritional status.
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