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High prevalence of small intestinal bacterial overgrowth in celiac patients with persistence of gastrointestinal symptoms after gluten withdrawal
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2003 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 98, No. 4, 2003 ISSN 0002-9270/03/$30.00 doi:10.1016/S0002-9270(03)00043-1
High Prevalence of Small Intestinal Bacterial Overgrowth in Celiac Patients With Persistence of Gastrointestinal Symptoms After Gluten Withdrawal Antonio Tursi, M.D., Giovanni Brandimarte, M.D., and GianMarco Giorgetti, M.D. Department of Emergency, “L. Bonomo” Hospital, Andria (BA); Department of Internal Medicine, Digestive Endoscopy Unit, “Cristo Re” Hospital, Rome; and Department of Internal Medicine, Artificial Nutrition Unit, “S. Eugenio” Hospital, Rome, Italy
OBJECTIVE: Celiac disease is a gluten-sensitive enteropathy with a broad spectrum of clinical manifestation, and most celiac patients respond to a gluten-free diet (GFD). However, in some rare cases celiacs continue to experience GI symptoms after GFD, despite optimal adherence to diet. The aim of our study was to evaluate the causes of persistence of GI symptoms in a series of consecutive celiac patients fully compliant to GFD. METHODS: We studied 15 celiac patients (five men, 10 women, mean age 36.5 yr, range 24 –59 yr) who continued to experience GI symptoms after at least 6 – 8 months of GFD (even if of less severity). Antigliadin antibody (AGA) test, antiendomysial antibody (EMA) test, and sorbitol H2breath test (H2-BT), as well as esophagogastroduodenoscopy (EGD) with histological evaluation, were performed before starting GFD. Bioptic samples were obtained from the second duodenal portion during EGD, and histopathology was expressed according to the Marsh classification. To investigate the causes of persistence of GI symptoms in these patients, we performed AGA and EMA tests, stool examination, EGD with histological examination of small bowel mucosa, and sorbitol-, lactose-, and lactulose H2breath tests. RESULTS: Histology improved in all patients after 6 – 8 months of GFD; therefore, refractory celiac disease could be excluded. One patient with Marsh II lesions was fully compliant to his diet but had mistakenly taken an antibiotic containing gluten. Two patients showed lactose malabsorption, one patient showed Giardia lamblia and one patient Ascaris lumbricoides infestation, and 10 patients showed small intestinal bacterial overgrowth (SIBO) by lactulose H2-BT. We prescribed a diet without milk or fresh milk– derived foods to the patient with lactose malabsorption; we treated the patients with parasite infestation with mebendazole 500 mg/day for 3 days for 2 consecutive wk; and we treated the patients with SIBO with rifaximin 800 mg/day for 1 wk. The patients were re-evaluated 1 month after the end of drug treatment (or after starting lactose-free diet); at this visit all patients were symptom-free.
CONCLUSIONS: This study showed that SIBO affects most celiacs with persistence of GI symptoms after gluten withdrawal. (Am J Gastroenterol 2003;98:839 – 843. © 2003 by Am. Coll. of Gastroenterology)
INTRODUCTION Celiac disease is a gluten-sensitive enteropathy with a broad spectrum of clinical manifestations, ranging from asymptomatic manifestation to typical malabsorptive symptoms, including with diarrhea, weight loss, and nutritional deficiencies (1). The vast majority of patients diagnosed with celiac disease respond to a gluten-free diet (GFD), with resolution of clinical symptoms and histological and serological recovery (2). However, in some rare cases celiac patients continue to experience GI symptoms after GFD, despite optimal adherence to diet. In these cases, several pathological conditions, ranging from lactose malabsorption to refractory celiac disease, may cause the persistence of symptoms (3). The aim of our study was to evaluate the causes of persistence of GI symptoms in a series of consecutive celiac patients fully compliant to GFD.
MATERIALS AND METHODS We studied 15 patients affected by celiac disease (five male, 10 female, mean age 36.5 yr, range 24 –59 yr) who continued to experience GI symptoms after at least 6 – 8 months of GFD, even if of less severity. All patients enrolled in this study showed a classical form of celiac disease, showing several GI symptoms (diarrhea [more than four bowel movements/day] in seven patients, slow gastric emptying in two patients, abdominal discomfort/abdominal pain with meteorism in six patients) and were fully compliant to diet. The symptoms were graded on a 4-point scale: 0 ⫽ absence of symptoms; 1 ⫽ slight symptoms; 2 ⫽ mild symptoms, 3 ⫽ severe symptoms. Nine patients showed grade 2 score and five grade 3 score before starting GFD (see Table 1), whereas eight showed grade 1 score, four showed grade 2
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AJG – Vol. 98, No. 4, 2003
Table 1. Patient Characteristics, Noninvasive Methods, and Intestinal Histology Before GFD
Patient No.
Sex
Age (yr)
1 2 3
F F M
24 34 30
4 5 6 7 8
M F F F F
28 42 30 37 42
9 10
M F
39 33
11
F
45
12 13
M F
48 27
14 15
F M
59 30
Symptoms
Grade
AGA
EMA
Sorbitol H2-BT
Histology (According to Marsh) (5)
Diarrhea Diarrhea Slow gastric emptying Abdominal pain Diarrhea Abdominal pain Diarrhea Slow gastric emptying Diarrhea Abdominal pain, meteorism Abdominal discomfort, meteorism Diarrhea Abdominal discomfort Diarrhea Abdominal pain, meteorism
2 2 3
⫹ ⫹ ⫺
⫹ ⫺ ⫹
⫹ ⫺ ⫹
IIIc IIIb IIIa
3 2 2 3 2
⫺ ⫹ ⫺ ⫺ ⫹
⫹ ⫹ ⫹ ⫺ ⫹
⫹ ⫹ ⫹ ⫹ ⫹
IIIb IIIc IIIc IIIa IIIb
2 3
⫺ ⫹
⫹ ⫹
⫹ ⫹
IIIa IIIc
2
⫹
⫹
⫹
IIIc
2 2
⫺ ⫺
⫺ ⫺
⫹ ⫹
IIIa IIIa
2 3
⫹ ⫺
⫹ ⫺
⫹ ⫺
IIIb IIIa
F ⫽ female; M ⫽ male.
score, and three showed grade 3 score after starting GFD (see Table 2). Diagnosis of celiac disease was made according to revised criteria of the European Society of Paediatric Gastroenterology and Nutrition (4). In all patients, we measured serum levels of IgA (nv 90 – 450 mg/dl) to exclude a condition of selective serum IgA deficiency before and after making diagnosis of celiac disease. IgA and IgG antigliadin antibodies (AGA) were measured in all patients before GFD starting, by ELISA (Alfa-gliatest, Eurospital, Trieste, Italy); IgA antiendomysial antibodies (EMA) were screened as well, by the indirect immunofluorescent method on monkey esophagus (Antiendomysium, Eurospital). We also performed a sorbitol H2-breath test (H2-BT) using 5 g sorbitol in 150 ml of tap water, collecting expiratory samples every 30 min for 4 h (MicroH2 Meter, Micro Medical, Rochester, UK), before starting GFD. We performed esophagogastroduodenoscopy in all patients before and then 6 – 8 months after starting GFD to assess histological recovery of small bowel. Bioptic samples (at least six) were obtained from the second duodenal portion during esophagogastroduodenoscopy and evaluated by ematoxylin/eosin coloration. Histopathology was expressed according to the Marsh classification of 1992 (5): “infiltrative” lesions with more than 30 lymphocytes per 100 epithelial cells are defined as Marsh type I, “infiltrative/hyperplastic” lesions as Marsh II,
and “partial (sub)total villous atrophy (VA)” as type III. We subdivided the Marsh III type into partial VA (Marsh IIIa), subtotal VA (Marsh IIIb), and total VA (Marsh IIIc). Other causes of VA, for example Giardia lamblia infection, tropical sprue, collagenous sprue, and food protein hypersensitivity (cow’s milks, eggs, fish, rice, chicken) (6), were excluded before making a diagnosis of celiac disease. Other causes of GI symptoms (e.g., exocrine pancreatic insufficiency) were also excluded before making a diagnosis of CD. To investigate the causes of persistence of GI symptoms in these celiacs despite full compliance to GFD, we performed the following tests: new evaluation of the serological tests (AGA and EMA), a stool examination for the presence of parasites or pathogen bacteria (three stool samples), an esophagogastroduodenoscopy with histological examination of small bowel mucosa, sorbitol- and lactose-H2breath tests and, finally, a lactulose H2-breath test to exclude small intestinal bacterial overgrowth (SIBO). In patients with diarrhea, we also performed a colonoscopy to exclude contemporary colonic disease (1). To perform H2-breath tests, all subjects were studied after an overnight fast, having been instructed to avoid foods likely to generate hydrogen for the 24 h before the test and to consume a meal of rice and meal; they were requested not to smoke on the morning of the test. End expiratory samples were collected before the patients drank the test solution (10 g lactulose, 5 g sorbitol, and 20 g lactose suspended in 150
AJG – April, 2003
Bacterial Overgrowth in Celiac Disease
841
Table 2. Patients’ Symptoms, Noninvasive Methods, and Intestinal Histology 6 – 8 Mo After GFD Patient No.
Symptoms
Grade
AGA
EMA
Marsh Histology
Lactose H2-BT
Sorbitol H2-BT
Lactulose H2-BT
Stool Examination
1
Unchanged
2
⫺
⫺
I
⫺
⫹
⫺
2
Persisting but less severe Persisting but less severe Unchanged Persisting but less severe Persisting but less severe Unchanged Persisting but less severe Persisting but less severe Unchanged
1
⫺
⫺
0
⫺
⫺
⫹
Giardia lamblia ⫺
2
⫺
⫺
0
⫺
⫺
⫹
⫺
3 1
⫺ ⫺
⫺ ⫺
0 0
⫺ ⫺
⫺ ⫺
⫹ ⫹
⫺
1
⫺
⫺
0
⫺
⫺
⫹
⫺
3 2
⫺ ⫺
⫺ ⫺
I 0
⫺ ⫺
⫺ ⫺
⫹ ⫹
⫺ ⫺
1
⫺
⫺
0
⫺
⫺
⫹
⫺
3
⫺
⫺
I
⫺
⫺
⫺
1
⫺
⫺
I
⫹
⫺
⫺
Ascaris lumbricoides ⫺
1
⫺
⫺
0
⫺
⫺
⫹
⫺
1
⫺
⫺
0
⫺
⫺
⫹
⫺
2
⫺
⫺
II
⫺
⫹
⫺
⫺
1
⫺
⫺
0
⫹
⫺
⫺
⫺
3 4 5 6 7 8 9 10 11 12 13 14 15
Persisting but less severe Persisting but less severe Persisting but less severe Persisting but less severe Persisting but less severe
Lactulose H2-BT ⫹ identifies a condition of SIBO.
ml of tap water) and at intervals (15 min for lactulose, 30 min for lactose and sorbitol) thereafter, for 4 h. Hydrogen concentrations in each collected sample were measured with a breath hydrogen analyzer (MicroH2 Meter). Regarding sorbitol and lactose H2-BT, an increase in H2 concentration of at least 20 ppm over fasting baseline was considered positive for sorbitol malabsorption. The cut-off for calculating the validity of the test was shifted every 30 min for lactose and sorbitol and every 15 min for lactulose H2-BT, and a response operating characteristics curve (7) was plotted on the basis of the obtained results. Regarding lactulose H2-BT, oral– cecal transit time was defined as the time elapsing between lactulose ingestion and a sustained increase of 10 ppm or more of H2 excretion above the baseline value, which is about 75 ⫾ 15 min (8). The presence of bacterial overgrowth was defined by the presence of a peak greater than 20 ppm occurring more than 15 min before the colonic peak; also, the patients with an elevated fasting H2 combined with an early increase in H2 after lactulose ingestion were considered positive for bacterial overgrowth (9).
RESULTS Histology improved in all patients after 6 – 8 months of GFD, and in none of them did we note persistence of severe histological lesions: six patients showed Marsh IIIc lesions,
four patients and five patients showed Marsh IIIb and IIIa lesions, respectively, before GFD (see Table 1), whereas 10 showed normal histology, one Marsh II and four Marsh I lesions after GFD. In light of these histological findings, refractory celiac disease could be excluded in all patients. In patients with diarrhea, colonoscopy with bioptic samples was performed to exclude contemporary colonic disease, and in all these patients histological evaluation showed normal colonic mucosa. Interestingly, in only one case was gluten assumption the cause of symptom persistence. The patient with Marsh II lesions (see Table 2) was fully compliant to diet, but he had mistakenly taken an unauthorized drug (an antibiotic containing gluten) for a long time. It is noteworthy that only sorbitol H2-BT was still positive in this patient, whereas AGA and EMA tests were negative despite accidental gluten assumption (see Table 2). As to the other causes of symptoms, two patients showed lactose malabsorption, one patient showed Giardia lamblia and one Ascaris lumbricoides infestation, and 10 patients showed SIBO by lactulose H2-BT (see Table 2). In these 14 patients, our next step was to treat the concomitant diseases to verify their role in symptom persistence. We prescribed a diet without milk or fresh milk– derived foods (such as fresh cheeses) to the patients with lactose malabsorption; we treated the patients with G. lamblia and
842
Tursi et al.
A. lumbricoides infestation with mebendazole 500 mg/day for 3 days for 2 consecutive wk; and we treated the patients with SIBO with rifaximin 800 mg/day for 1 wk. The patients were re-evaluated 1 month after the end of drug treatment (or after starting lactose-free diet). All of them were finally symptom-free, and all tests (sorbitol and lactulose H2-BT, stool examination, and AGA and EMA evaluation) were negative. Lactose H2-BT persisted positive in patients with lactose intolerance, but the patients were symptom-free thanks to lactose withdrawal.
DISCUSSION In most of celiac patients, GFD results in both resolution of clinical symptoms and histological recovery, with seroconversion of AGA and EMA and negativity of sorbitol H2-BT. However, in some rare cases patients complaining of GI symptoms with histological findings consistent with celiac disease are unable to achieve remission of symptoms despite full adherence to GFD, and in these cases other causes of GI symptoms should be considered. In these cases, the first hypothesis may be a dietary mistake, which often occurs despite patients’ adherence to GFD. This hypothesis is confirmed in this study by the patient who had mistakenly taken an antibiotic containing gluten. Another cause may be a parasitic infestation. Although parasitic infestation (especially G. lamblia infestation) is always excluded before making diagnosis of celiac disease, in some cases it may occur after starting GFD and may cause persistence or worsening of GI symptoms. This occurrence has been confirmed in this study, in which two of 15 patients (13.33%) showed parasitic infestation after diagnosis of celiac disease and during GFD. In these cases, it is very important to investigate all family members, because parasitic infestations may asymptomatically affect individuals of the same family, who can perpetuate the infestation by oral–fecal route (10). In fact, one patient’s wife and one son were both positive for A. lumbricoides infestation (the subjects reported consumption of vegetables not correctly washed). Lactose intolerance may also perpetuate GI symptoms after GFD. We routinely perform lactose H2-BT in all celiacs at the time of diagnosis to start a correct diet, but both the patients with lactose intolerance in this study refused lactose H2-BT before starting GFD. The most dangerous cause of GI symptom persistence after GFD in celiacs is refractory celiac disease. According to Ryan’s definition, patients with persistence of symptoms and histological lesions despite GFD should be affected by primary refractory celiac disease (11). Although O’Mahoney et al. estimate that 7– 8% of adult celiac patients have refractory celiac disease (12), in our study, fortunately, none of the patients developed this severe disease. In fact, we observed a histological improvement in all
AJG – Vol. 98, No. 4, 2003
patients despite persistence of symptoms (even if of less severity). Thus, we needed to look for another cause of persistent symptoms in these patients, which led us to the most interesting finding of this study. Of 15 celiac patients, 10 (66.66%) with persistent GI symptoms showed SIBO, and the eradication of SIBO led to the disappearance of symptoms. This is a very important finding, because demonstration of SIBO in celiacs with persistent GI symptoms and subsequent eradication of SIBO may resolve the clinical picture and thus remove suspicion of refractory celiac disease. There are no data regarding either the prevalence of SIBO in the general celiac population or the causes predisposing to development of SIBO in celiacs. However, it is hypothesized that disturbed motility of the GI tract in celiacs is the main etiological factor in development of SIBO. Consistent data are available on the presence of a disturbed motility of the esophagus (13, 14), stomach (15, 16), small intestine (17–19), gallbladder (20, 21), and colon (22) of untreated celiac patients. Motility disorders of the gut are a predisposing factor in the development of SIBO (23) and may contribute to development of symptoms in some untreated celiacs and to persistence of symptoms after GFD in some of them. In fact, SIBO is characterized by nonspecific GI complaints, ranging from mild symptoms, such as bloating, abdominal pain, and flatulence, to severe malabsorption syndrome with diarrhea, steatorrhea, and weight loss, with small intestinal mucosal lesions in some cases (24). Bacteria are responsible for intraluminal sugar fermentation with production of a great amount of H2 and CH4 (causing bloating, abdominal pain, and flatulence). Furthermore, they cause bile salts’ deconjugation and dehydroxilation of fatty acids, with consequent fat malabsorption and impaired ileal resorption of bile acids, which have irritative and cathartic effects on colonic mucosa. The final consequence of these events is the development of diarrhea, abdominal pain, and mucus passage with stool. These symptoms are indistinguishable from those of classic celiac disease and may mask a patient’s poor compliance to diet or development of refractory celiac disease. However, correct diagnosis and treatment of other causes of symptom persistence in some celiacs after GFD may easily exclude so dramatic a complication in most cases. Someone may object that direct culture and not lactulose H2-BT is the gold standard in diagnosing SIBO, because its sensitivity is reported to be between 16% and 61% (25, 26). However, two considerations overcome this possible objection. First of all, direct culture is restricted to the proximal small intestine: in the absence of substantial hypochlorhydria, SIBO often results from migration of colonic flora and therefore we can intuitively detect higher levels of bacteria only in the ileal area, which is very difficult to sample. Conversely, lactulose H2-BT allows determination of SIBO in all areas of potential involvement. Second, clinical criteria permit to overcome every possible speculation about the role of SIBO in perpetuate gastrointestinal symptoms in
AJG – April, 2003
celiacs on GFD: all celiac patients with SIBOwere successfully treated with a nonadsorbable antibiotic (rifaximin), with complete resolution of symptoms after the therapy. The only risk in these cases is that celiac patients with disappearance of GI symptoms after SIBO eradication may underestimate the role of diet. In fact, these patients could attribute the symptoms to SIBO only, because they experience benefits only by SIBO eradication and not by GFD. Because symptom disappearance is a very important factor in obtaining a patients’ complete adherence to diet, gastroenterologists should play a key role, explaining to patients the possible coexistence of both these pathological conditions and explaining the great importance of maintaining a correct GFD to prevent neoplastic and non-neoplastic complications of celiac disease. In conclusion, this study showed that SIBO is the most frequent cause of GI symptom persistence in celiacs after gluten withdrawal. Motility disorders, a predisposing factor in development of SIBO, may affect celiac disease: therefore, SIBO investigation could be performed in all celiac patients before starting GFD; SIBO should always be carefully checked in cases with persistent GI symptoms after starting GFD, to obtain resolution of symptoms after adequate antibiotic therapy if SIBO is confirmed.
Bacterial Overgrowth in Celiac Disease
9.
10.
11. 12.
13.
14.
15.
16.
17.
18. Reprint requests and correspondence: Antonio Tursi, M.D., Department of Emergency, L. Bonomo Hospital, Galleria Pisani 4, 70031 (BA) Andria, Italy. Received Dec. 21, 2001; accepted Apr. 12, 2002.
19.
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20.
1. Tursi A, Giorgetti GM, Brandimarte G, et al. Prevalence and clinical presentation of subclinical/silent coeliac disease in adults: An analysis on a 12-year observation. Hepatogastroenterol 2001;39:462–4. 2. Trier JS. Celiac sprue. N Engl J Med 1991;325:1709 –19. 3. Fine KD, Meyer RL, Lee EL. The prevalence and causes of chronic diarrhea in patients with celiac sprue treated with gluten-free diet. Gastroenterology 1997;112:1830 –8. 4. Working Group of European Society of Paediatric Gastroenterology and Nutrition. Revised criteria for diagnosis of coeliac disease. Arch Dis Child 1990;65:909 –11. 5. Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunologic approach to the spectrum of gluten sensitivity (celiac sprue). Gastroenterology 1992;102:330 –54. 6. Oberhuber G, Grandisch G, Vogelsang H. The histopathology of coeliac disease: Time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol 1999;11:1185–94. 7. Sackett DL, Haynes RB, Tugwell B. Clinical epidemiology. A basic science for clinical medicine. Boston: Little Brown, 1985:59 –138. 8. Hirikawa M, Iida M, Korogi N, Fujishima M. Hydrogen breath
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test assessment of oro-cecal transit time: Comparison with barium meal study. Am J Gastroenterol 1988;83:1361–3. Kerlin P, Wong L. Breath hydrogen testing in bacterial overgrowth of the small intestine. Gastroenterology 1988;95:982–8. Kappus KD, Lundgren RG Jr, Juranek DD, et al. Intestinal parasitism in the United States: Update on a continuing problem. Am J Trop Med Hyg 1994;50:705–13. Ryan BM, Keheller D. Refractory celiac disease. Gastroenterology 2000;119:243–51. O’Mahoney S, Howdle P, Losowsky M. Review article: Management of patients with non-responsive celiac disease. Aliment Pharmacol Ther 1996;10:671–8. Usai P, Usai Satta P, Lai M, et al. Autonomic dysfunction and upper digestive functional disorders in untreated adult celiac disease. Eur J Clin Invest 1997;27:1009 –15. Iovino P, Ciacci C, Sabbatini F, et al. Esophageal impairment in adult celiac disease with steatorrhea. Am J Gastroenterol 1998;93:1243–9. Giorgetti GM, Tursi A, Brandimarte G, et al. Dysmotility-like dyspeptic symptoms in coeliac patients: Role of gluten and Helicobacter pylori infection. Dig Liver Dis 2000;32:73–4. Benini L, Sembenini C, Salandini L, et al. Gastric emptying of realistic meals with and without gluten in patients with coeliac disease. Effect of jejunal mucosal recovery. Scand J Gastroenterol 2001;36:1044 –8. Bassotti G, Castellucci G, Betti C, et al. Abnormal gastrointestinal motility in patients with celiac sprue. Dig Dis Sci 1994;39:1947–54. Spiller RC, Lee YC, Edge C, et al. Delayed mouth-caecum transit of a lactulose labelled liquid test meal in patients with steatorrhea caused by partially treated coeliac disease. Gut 1987;28:1275–82. 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 1997;42:2100 –5. Maton PN, Selden AC, Fitzpatrick ML, Chadwick VS. Defective gallbladder emptying and cholecystokinin release in celiac disease. Reversal by gluten-free diet. Gastroenterology 1985;88:391–6. Fraquelli M, Bardella MT, Peracchi M, et al. Gallbladder emptying and somatostatin and cholecystokinin plasma levels in celiac disease. Am J Gastroenterol 1999;94:1866 –70. Bai JC, Maurino E, Martinez C, et al. Abnormal colonic transit time in untreated celiac sprue. Acta Gastroenterol Latinoam 1995;25:277–84. Husebye E. Gastrointestinal motility disorders and bacterial overgrowth. J Intern Med 1995;237:419 –27. Haboubi NY, Lee GS, Montgomery RD. Duodenal mucosa morphometry of elderly patients with small intestinal bacterial overgrowth: Response to antibiotic treatment. Age Ageing 1991;20:29 –32. Riorden SM, McIver CJ, Walker BM, et al. The lactulose breath hydrogen test and small intestinal bacterial overgrowth. Am J Gastroenterol 1996;91:1795–803. Corazza GR, Strocchi A, Sorge M, et al. Prevalence and consistency of low breath H2 excretion following lactose ingestion. Possible implications for the clinical use of the H2 breath test. Dig Dis Sci 1993;38:2010 –6.
Vol. 98, No. 4, 2003 ISSN 0002-9270/03/$30.00 doi:10.1016/S0002-9270(03)00043-1
High Prevalence of Small Intestinal Bacterial Overgrowth in Celiac Patients With Persistence of Gastrointestinal Symptoms After Gluten Withdrawal Antonio Tursi, M.D., Giovanni Brandimarte, M.D., and GianMarco Giorgetti, M.D. Department of Emergency, “L. Bonomo” Hospital, Andria (BA); Department of Internal Medicine, Digestive Endoscopy Unit, “Cristo Re” Hospital, Rome; and Department of Internal Medicine, Artificial Nutrition Unit, “S. Eugenio” Hospital, Rome, Italy
OBJECTIVE: Celiac disease is a gluten-sensitive enteropathy with a broad spectrum of clinical manifestation, and most celiac patients respond to a gluten-free diet (GFD). However, in some rare cases celiacs continue to experience GI symptoms after GFD, despite optimal adherence to diet. The aim of our study was to evaluate the causes of persistence of GI symptoms in a series of consecutive celiac patients fully compliant to GFD. METHODS: We studied 15 celiac patients (five men, 10 women, mean age 36.5 yr, range 24 –59 yr) who continued to experience GI symptoms after at least 6 – 8 months of GFD (even if of less severity). Antigliadin antibody (AGA) test, antiendomysial antibody (EMA) test, and sorbitol H2breath test (H2-BT), as well as esophagogastroduodenoscopy (EGD) with histological evaluation, were performed before starting GFD. Bioptic samples were obtained from the second duodenal portion during EGD, and histopathology was expressed according to the Marsh classification. To investigate the causes of persistence of GI symptoms in these patients, we performed AGA and EMA tests, stool examination, EGD with histological examination of small bowel mucosa, and sorbitol-, lactose-, and lactulose H2breath tests. RESULTS: Histology improved in all patients after 6 – 8 months of GFD; therefore, refractory celiac disease could be excluded. One patient with Marsh II lesions was fully compliant to his diet but had mistakenly taken an antibiotic containing gluten. Two patients showed lactose malabsorption, one patient showed Giardia lamblia and one patient Ascaris lumbricoides infestation, and 10 patients showed small intestinal bacterial overgrowth (SIBO) by lactulose H2-BT. We prescribed a diet without milk or fresh milk– derived foods to the patient with lactose malabsorption; we treated the patients with parasite infestation with mebendazole 500 mg/day for 3 days for 2 consecutive wk; and we treated the patients with SIBO with rifaximin 800 mg/day for 1 wk. The patients were re-evaluated 1 month after the end of drug treatment (or after starting lactose-free diet); at this visit all patients were symptom-free.
CONCLUSIONS: This study showed that SIBO affects most celiacs with persistence of GI symptoms after gluten withdrawal. (Am J Gastroenterol 2003;98:839 – 843. © 2003 by Am. Coll. of Gastroenterology)
INTRODUCTION Celiac disease is a gluten-sensitive enteropathy with a broad spectrum of clinical manifestations, ranging from asymptomatic manifestation to typical malabsorptive symptoms, including with diarrhea, weight loss, and nutritional deficiencies (1). The vast majority of patients diagnosed with celiac disease respond to a gluten-free diet (GFD), with resolution of clinical symptoms and histological and serological recovery (2). However, in some rare cases celiac patients continue to experience GI symptoms after GFD, despite optimal adherence to diet. In these cases, several pathological conditions, ranging from lactose malabsorption to refractory celiac disease, may cause the persistence of symptoms (3). The aim of our study was to evaluate the causes of persistence of GI symptoms in a series of consecutive celiac patients fully compliant to GFD.
MATERIALS AND METHODS We studied 15 patients affected by celiac disease (five male, 10 female, mean age 36.5 yr, range 24 –59 yr) who continued to experience GI symptoms after at least 6 – 8 months of GFD, even if of less severity. All patients enrolled in this study showed a classical form of celiac disease, showing several GI symptoms (diarrhea [more than four bowel movements/day] in seven patients, slow gastric emptying in two patients, abdominal discomfort/abdominal pain with meteorism in six patients) and were fully compliant to diet. The symptoms were graded on a 4-point scale: 0 ⫽ absence of symptoms; 1 ⫽ slight symptoms; 2 ⫽ mild symptoms, 3 ⫽ severe symptoms. Nine patients showed grade 2 score and five grade 3 score before starting GFD (see Table 1), whereas eight showed grade 1 score, four showed grade 2
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AJG – Vol. 98, No. 4, 2003
Table 1. Patient Characteristics, Noninvasive Methods, and Intestinal Histology Before GFD
Patient No.
Sex
Age (yr)
1 2 3
F F M
24 34 30
4 5 6 7 8
M F F F F
28 42 30 37 42
9 10
M F
39 33
11
F
45
12 13
M F
48 27
14 15
F M
59 30
Symptoms
Grade
AGA
EMA
Sorbitol H2-BT
Histology (According to Marsh) (5)
Diarrhea Diarrhea Slow gastric emptying Abdominal pain Diarrhea Abdominal pain Diarrhea Slow gastric emptying Diarrhea Abdominal pain, meteorism Abdominal discomfort, meteorism Diarrhea Abdominal discomfort Diarrhea Abdominal pain, meteorism
2 2 3
⫹ ⫹ ⫺
⫹ ⫺ ⫹
⫹ ⫺ ⫹
IIIc IIIb IIIa
3 2 2 3 2
⫺ ⫹ ⫺ ⫺ ⫹
⫹ ⫹ ⫹ ⫺ ⫹
⫹ ⫹ ⫹ ⫹ ⫹
IIIb IIIc IIIc IIIa IIIb
2 3
⫺ ⫹
⫹ ⫹
⫹ ⫹
IIIa IIIc
2
⫹
⫹
⫹
IIIc
2 2
⫺ ⫺
⫺ ⫺
⫹ ⫹
IIIa IIIa
2 3
⫹ ⫺
⫹ ⫺
⫹ ⫺
IIIb IIIa
F ⫽ female; M ⫽ male.
score, and three showed grade 3 score after starting GFD (see Table 2). Diagnosis of celiac disease was made according to revised criteria of the European Society of Paediatric Gastroenterology and Nutrition (4). In all patients, we measured serum levels of IgA (nv 90 – 450 mg/dl) to exclude a condition of selective serum IgA deficiency before and after making diagnosis of celiac disease. IgA and IgG antigliadin antibodies (AGA) were measured in all patients before GFD starting, by ELISA (Alfa-gliatest, Eurospital, Trieste, Italy); IgA antiendomysial antibodies (EMA) were screened as well, by the indirect immunofluorescent method on monkey esophagus (Antiendomysium, Eurospital). We also performed a sorbitol H2-breath test (H2-BT) using 5 g sorbitol in 150 ml of tap water, collecting expiratory samples every 30 min for 4 h (MicroH2 Meter, Micro Medical, Rochester, UK), before starting GFD. We performed esophagogastroduodenoscopy in all patients before and then 6 – 8 months after starting GFD to assess histological recovery of small bowel. Bioptic samples (at least six) were obtained from the second duodenal portion during esophagogastroduodenoscopy and evaluated by ematoxylin/eosin coloration. Histopathology was expressed according to the Marsh classification of 1992 (5): “infiltrative” lesions with more than 30 lymphocytes per 100 epithelial cells are defined as Marsh type I, “infiltrative/hyperplastic” lesions as Marsh II,
and “partial (sub)total villous atrophy (VA)” as type III. We subdivided the Marsh III type into partial VA (Marsh IIIa), subtotal VA (Marsh IIIb), and total VA (Marsh IIIc). Other causes of VA, for example Giardia lamblia infection, tropical sprue, collagenous sprue, and food protein hypersensitivity (cow’s milks, eggs, fish, rice, chicken) (6), were excluded before making a diagnosis of celiac disease. Other causes of GI symptoms (e.g., exocrine pancreatic insufficiency) were also excluded before making a diagnosis of CD. To investigate the causes of persistence of GI symptoms in these celiacs despite full compliance to GFD, we performed the following tests: new evaluation of the serological tests (AGA and EMA), a stool examination for the presence of parasites or pathogen bacteria (three stool samples), an esophagogastroduodenoscopy with histological examination of small bowel mucosa, sorbitol- and lactose-H2breath tests and, finally, a lactulose H2-breath test to exclude small intestinal bacterial overgrowth (SIBO). In patients with diarrhea, we also performed a colonoscopy to exclude contemporary colonic disease (1). To perform H2-breath tests, all subjects were studied after an overnight fast, having been instructed to avoid foods likely to generate hydrogen for the 24 h before the test and to consume a meal of rice and meal; they were requested not to smoke on the morning of the test. End expiratory samples were collected before the patients drank the test solution (10 g lactulose, 5 g sorbitol, and 20 g lactose suspended in 150
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Table 2. Patients’ Symptoms, Noninvasive Methods, and Intestinal Histology 6 – 8 Mo After GFD Patient No.
Symptoms
Grade
AGA
EMA
Marsh Histology
Lactose H2-BT
Sorbitol H2-BT
Lactulose H2-BT
Stool Examination
1
Unchanged
2
⫺
⫺
I
⫺
⫹
⫺
2
Persisting but less severe Persisting but less severe Unchanged Persisting but less severe Persisting but less severe Unchanged Persisting but less severe Persisting but less severe Unchanged
1
⫺
⫺
0
⫺
⫺
⫹
Giardia lamblia ⫺
2
⫺
⫺
0
⫺
⫺
⫹
⫺
3 1
⫺ ⫺
⫺ ⫺
0 0
⫺ ⫺
⫺ ⫺
⫹ ⫹
⫺
1
⫺
⫺
0
⫺
⫺
⫹
⫺
3 2
⫺ ⫺
⫺ ⫺
I 0
⫺ ⫺
⫺ ⫺
⫹ ⫹
⫺ ⫺
1
⫺
⫺
0
⫺
⫺
⫹
⫺
3
⫺
⫺
I
⫺
⫺
⫺
1
⫺
⫺
I
⫹
⫺
⫺
Ascaris lumbricoides ⫺
1
⫺
⫺
0
⫺
⫺
⫹
⫺
1
⫺
⫺
0
⫺
⫺
⫹
⫺
2
⫺
⫺
II
⫺
⫹
⫺
⫺
1
⫺
⫺
0
⫹
⫺
⫺
⫺
3 4 5 6 7 8 9 10 11 12 13 14 15
Persisting but less severe Persisting but less severe Persisting but less severe Persisting but less severe Persisting but less severe
Lactulose H2-BT ⫹ identifies a condition of SIBO.
ml of tap water) and at intervals (15 min for lactulose, 30 min for lactose and sorbitol) thereafter, for 4 h. Hydrogen concentrations in each collected sample were measured with a breath hydrogen analyzer (MicroH2 Meter). Regarding sorbitol and lactose H2-BT, an increase in H2 concentration of at least 20 ppm over fasting baseline was considered positive for sorbitol malabsorption. The cut-off for calculating the validity of the test was shifted every 30 min for lactose and sorbitol and every 15 min for lactulose H2-BT, and a response operating characteristics curve (7) was plotted on the basis of the obtained results. Regarding lactulose H2-BT, oral– cecal transit time was defined as the time elapsing between lactulose ingestion and a sustained increase of 10 ppm or more of H2 excretion above the baseline value, which is about 75 ⫾ 15 min (8). The presence of bacterial overgrowth was defined by the presence of a peak greater than 20 ppm occurring more than 15 min before the colonic peak; also, the patients with an elevated fasting H2 combined with an early increase in H2 after lactulose ingestion were considered positive for bacterial overgrowth (9).
RESULTS Histology improved in all patients after 6 – 8 months of GFD, and in none of them did we note persistence of severe histological lesions: six patients showed Marsh IIIc lesions,
four patients and five patients showed Marsh IIIb and IIIa lesions, respectively, before GFD (see Table 1), whereas 10 showed normal histology, one Marsh II and four Marsh I lesions after GFD. In light of these histological findings, refractory celiac disease could be excluded in all patients. In patients with diarrhea, colonoscopy with bioptic samples was performed to exclude contemporary colonic disease, and in all these patients histological evaluation showed normal colonic mucosa. Interestingly, in only one case was gluten assumption the cause of symptom persistence. The patient with Marsh II lesions (see Table 2) was fully compliant to diet, but he had mistakenly taken an unauthorized drug (an antibiotic containing gluten) for a long time. It is noteworthy that only sorbitol H2-BT was still positive in this patient, whereas AGA and EMA tests were negative despite accidental gluten assumption (see Table 2). As to the other causes of symptoms, two patients showed lactose malabsorption, one patient showed Giardia lamblia and one Ascaris lumbricoides infestation, and 10 patients showed SIBO by lactulose H2-BT (see Table 2). In these 14 patients, our next step was to treat the concomitant diseases to verify their role in symptom persistence. We prescribed a diet without milk or fresh milk– derived foods (such as fresh cheeses) to the patients with lactose malabsorption; we treated the patients with G. lamblia and
842
Tursi et al.
A. lumbricoides infestation with mebendazole 500 mg/day for 3 days for 2 consecutive wk; and we treated the patients with SIBO with rifaximin 800 mg/day for 1 wk. The patients were re-evaluated 1 month after the end of drug treatment (or after starting lactose-free diet). All of them were finally symptom-free, and all tests (sorbitol and lactulose H2-BT, stool examination, and AGA and EMA evaluation) were negative. Lactose H2-BT persisted positive in patients with lactose intolerance, but the patients were symptom-free thanks to lactose withdrawal.
DISCUSSION In most of celiac patients, GFD results in both resolution of clinical symptoms and histological recovery, with seroconversion of AGA and EMA and negativity of sorbitol H2-BT. However, in some rare cases patients complaining of GI symptoms with histological findings consistent with celiac disease are unable to achieve remission of symptoms despite full adherence to GFD, and in these cases other causes of GI symptoms should be considered. In these cases, the first hypothesis may be a dietary mistake, which often occurs despite patients’ adherence to GFD. This hypothesis is confirmed in this study by the patient who had mistakenly taken an antibiotic containing gluten. Another cause may be a parasitic infestation. Although parasitic infestation (especially G. lamblia infestation) is always excluded before making diagnosis of celiac disease, in some cases it may occur after starting GFD and may cause persistence or worsening of GI symptoms. This occurrence has been confirmed in this study, in which two of 15 patients (13.33%) showed parasitic infestation after diagnosis of celiac disease and during GFD. In these cases, it is very important to investigate all family members, because parasitic infestations may asymptomatically affect individuals of the same family, who can perpetuate the infestation by oral–fecal route (10). In fact, one patient’s wife and one son were both positive for A. lumbricoides infestation (the subjects reported consumption of vegetables not correctly washed). Lactose intolerance may also perpetuate GI symptoms after GFD. We routinely perform lactose H2-BT in all celiacs at the time of diagnosis to start a correct diet, but both the patients with lactose intolerance in this study refused lactose H2-BT before starting GFD. The most dangerous cause of GI symptom persistence after GFD in celiacs is refractory celiac disease. According to Ryan’s definition, patients with persistence of symptoms and histological lesions despite GFD should be affected by primary refractory celiac disease (11). Although O’Mahoney et al. estimate that 7– 8% of adult celiac patients have refractory celiac disease (12), in our study, fortunately, none of the patients developed this severe disease. In fact, we observed a histological improvement in all
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patients despite persistence of symptoms (even if of less severity). Thus, we needed to look for another cause of persistent symptoms in these patients, which led us to the most interesting finding of this study. Of 15 celiac patients, 10 (66.66%) with persistent GI symptoms showed SIBO, and the eradication of SIBO led to the disappearance of symptoms. This is a very important finding, because demonstration of SIBO in celiacs with persistent GI symptoms and subsequent eradication of SIBO may resolve the clinical picture and thus remove suspicion of refractory celiac disease. There are no data regarding either the prevalence of SIBO in the general celiac population or the causes predisposing to development of SIBO in celiacs. However, it is hypothesized that disturbed motility of the GI tract in celiacs is the main etiological factor in development of SIBO. Consistent data are available on the presence of a disturbed motility of the esophagus (13, 14), stomach (15, 16), small intestine (17–19), gallbladder (20, 21), and colon (22) of untreated celiac patients. Motility disorders of the gut are a predisposing factor in the development of SIBO (23) and may contribute to development of symptoms in some untreated celiacs and to persistence of symptoms after GFD in some of them. In fact, SIBO is characterized by nonspecific GI complaints, ranging from mild symptoms, such as bloating, abdominal pain, and flatulence, to severe malabsorption syndrome with diarrhea, steatorrhea, and weight loss, with small intestinal mucosal lesions in some cases (24). Bacteria are responsible for intraluminal sugar fermentation with production of a great amount of H2 and CH4 (causing bloating, abdominal pain, and flatulence). Furthermore, they cause bile salts’ deconjugation and dehydroxilation of fatty acids, with consequent fat malabsorption and impaired ileal resorption of bile acids, which have irritative and cathartic effects on colonic mucosa. The final consequence of these events is the development of diarrhea, abdominal pain, and mucus passage with stool. These symptoms are indistinguishable from those of classic celiac disease and may mask a patient’s poor compliance to diet or development of refractory celiac disease. However, correct diagnosis and treatment of other causes of symptom persistence in some celiacs after GFD may easily exclude so dramatic a complication in most cases. Someone may object that direct culture and not lactulose H2-BT is the gold standard in diagnosing SIBO, because its sensitivity is reported to be between 16% and 61% (25, 26). However, two considerations overcome this possible objection. First of all, direct culture is restricted to the proximal small intestine: in the absence of substantial hypochlorhydria, SIBO often results from migration of colonic flora and therefore we can intuitively detect higher levels of bacteria only in the ileal area, which is very difficult to sample. Conversely, lactulose H2-BT allows determination of SIBO in all areas of potential involvement. Second, clinical criteria permit to overcome every possible speculation about the role of SIBO in perpetuate gastrointestinal symptoms in
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celiacs on GFD: all celiac patients with SIBOwere successfully treated with a nonadsorbable antibiotic (rifaximin), with complete resolution of symptoms after the therapy. The only risk in these cases is that celiac patients with disappearance of GI symptoms after SIBO eradication may underestimate the role of diet. In fact, these patients could attribute the symptoms to SIBO only, because they experience benefits only by SIBO eradication and not by GFD. Because symptom disappearance is a very important factor in obtaining a patients’ complete adherence to diet, gastroenterologists should play a key role, explaining to patients the possible coexistence of both these pathological conditions and explaining the great importance of maintaining a correct GFD to prevent neoplastic and non-neoplastic complications of celiac disease. In conclusion, this study showed that SIBO is the most frequent cause of GI symptom persistence in celiacs after gluten withdrawal. Motility disorders, a predisposing factor in development of SIBO, may affect celiac disease: therefore, SIBO investigation could be performed in all celiac patients before starting GFD; SIBO should always be carefully checked in cases with persistent GI symptoms after starting GFD, to obtain resolution of symptoms after adequate antibiotic therapy if SIBO is confirmed.
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10.
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17.
18. Reprint requests and correspondence: Antonio Tursi, M.D., Department of Emergency, L. Bonomo Hospital, Galleria Pisani 4, 70031 (BA) Andria, Italy. Received Dec. 21, 2001; accepted Apr. 12, 2002.
19.
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