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Evidence of Prolonged Orocecal Transit Time and Small Intestinal Bacterial Overgrowth in Acromegalic Patients

Department of Endocrine & Medical Sciences and Center of Excellence for Biomedical Research (E.R., A.R., F.M., D.F.), and Department of Gastroenterology (A.P., V.S., A.G.), University of Genova, 16132 Genova, Italy

Address all correspondence and requests for reprints to: Diego Ferone, M.D., Ph.D., Department of Endocrine & Medical Sciences (DiSEM), University of Genova, viale Benedetto XV, 6, 16132 Genova, Italy. E-mail: ferone{at}unige.it.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: Gastrointestinal abnormalities in acromegaly include dolichomegacolon, slow colonic transit, and increased prevalence of colonic polyps. Conversely, no data are available on the small intestine.

Objective: The aim of the study was to investigate the orocecal transit time (OCTT) and the presence of small intestinal bacterial overgrowth (SIBO).

Patients: A total of 41 acromegalic patients and 30 sex- and age-matched control subjects entered the study. Acromegalic patients were classified according to the medical treatment with somatostatin analogs as "treated" (n = 22) and "untreated" (n = 19), whereas according to the disease control, as "controlled" (n = 17), "uncontrolled" (n = 10), and "partially controlled" (n = 14). Patients and controls completed a questionnaire and underwent a standardized 10-g lactulose hydrogen breath test to determine the OCTT and presence of SIBO. SIBO-positive patients underwent eradication with rifaximine.

Results: An increased prevalence of SIBO (18 of 41 vs. 1 of 30; P < 0.0001) and a significantly delayed OCTT (169.53 ± 8.15 vs. 107.25 ± 6.56 min; P < 0.0001) were evidenced in patients compared with controls. No significant statistical differences were found between "treated" or "untreated" patients positive for SIBO or between "controlled," "partially controlled," and "uncontrolled" patients. OCTT was significantly delayed in "treated" vs. "untreated" patients (183.21 ± 9.01 and 158.89 ± 6.38, respectively; P = 0.02) and in patients compared with controls (105.75 ± 6.34; P < 0.0001). Rifaximine eradicated SIBO in more than 50% of patients who underwent treatment.

Conclusions: These data demonstrate for the first time that SIBO occurs more frequently in acromegalic patients, however, it can be successfully treated by a specific antibiotic. Medical therapy with somatostatin analogs does not affect SIBO prevalence. OCTT resulted significantly prolonged in both "treated" and "untreated" patients, suggesting that acromegaly determines per se an impairment of the intestinal motility. Indeed, disease control seems irrelevant on the delayed OCTT, suggesting that this alteration might be an irreversible complication of acromegaly, probably related to an autonomic intestinal disorder, as we have previously demonstrated at the cardiac level.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
ACROMEGALY, A RARE, slow-developing disease due to GH/IGF-I excess because of a pituitary tumor (>98% of cases) is associated with gastrointestinal complications (1). The most important is a higher prevalence of colonic polyps and cancer compared with the normal population (2). Moreover, acromegalic patients present a prolonged colonic transit and an increased production of deoxycholic acid that are linked to formation of cholecystic cholesterinic stones, especially during long-term treatment with somatostatin analogs (SSAs) (3). It is known that somatostatin influences intestinal motility, and regulates the secretion and absorption of water and electrolytes in the bowel (4). Indeed, sc administration of the SSA octreotide reduces antral motility and determines a delay in gastric emptying (5). Furthermore, it induces phase III motor complexes in the small intestine that are physiologically responsible for the intestinal clearance in the interprandial phase, both in healthy subjects and in patients affected by intestinal motor alterations, such as in scleroderma (6). However, no data are available on small intestine motility and possible alterations of the intestinal bacterial flora in acromegalic patients.

In physiological conditions, bacterial concentration increases progressively starting from the proximal portions of the alimentary canal to the more distal sites. The quality and amount of the intestinal bacterial flora play an important role in the organism homeostasis. Small intestinal bacterial overgrowth (SIBO) represents a paradigmatic condition of quantitative intestinal microbial flora imbalance and atypical microorganisms localization (7, 8, 9). SIBO is defined as the presence of altered microbial concentrations (>10⁵ colony forming unit/ml) in the jejunal aspirate, and is caused by numerous predisposing diseases, including the reduction of gastric acid secretion, intestinal motor and anatomic abnormalities, and immune function impairment (10). SIBO shows a clinical spectrum varying from completely asymptomatic status, to severe malabsorption syndrome characterized by steatorrhea, multiple nutritional deficits, and weight loss (11, 12, 13). Although the gold standard analysis for the diagnosis of SIBO is the jejunal aspirate culture, a complex and invasive technique, in the clinical practice, glucose and lactulose hydrogen (H₂) breath tests represent noninvasive and cheap valid diagnostic tools as well (12, 14, 15, 16, 17). SIBO treatment consists of the eradication of the bacterial overgrowth with antibiotics, followed by the correction of possible nutritional deficits, and, when achievable, of potential predisposing factors (18, 19).

SIBO presents most frequently with unspecific intestinal symptoms as meteorism, abdominal distension, flatulence, abdominal pain, and diarrhea, which make the picture hardly discernable from that of the irritable bowel syndrome. Clinical experience shows that some of these intestinal symptoms are often observed in patients with acromegaly.

The aims of this study were to examine the intestinal motility, by estimating the orocecal transit time (OCTT), and to evaluate the prevalence of SIBO in acromegalic patients.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

A total of 41 acromegalic patients (17 male and 24 female, mean age 56.3 ± 3.1 yr) and 30 age- and sex-matched healthy subjects (11 male and 19 female, mean age 47.9 ± 4.6 yr, asymptomatic for intestinal disorders), were enrolled in the study. Patients’ biochemical and fecal profile was evaluated before entering the study to exclude the presence of malabsorption and was normal in all of them.

The study protocol was approved by the local ethical committee, and a written informed consent was obtained from all patients.

Of the 41 patients, 27 previously underwent transsphenoidal surgery that resulted curative in only 14. These latter 14 patients were not having any medical therapy at study entry. The remaining 13 patients, not cured with surgery, were treated with SSAs. There were 10 patients in primary medical therapy with SSAs, however, one of them first underwent radiotherapy and then started SSA treatment. Four newly diagnosed patients were untreated at the time of enrollment in the study (naive patients). Patients treated with SSAs at study entry were classified as "treated" (n = 22), and patients without any medical therapy at study entry were classified as "untreated" (n = 19).

Disease activity was defined by serum GH levels after oral glucose tolerance test, with a single blood sample at the 120th minute (20), and plasma IGF-I levels for age. On the basis of disease control, patients were subdivided in "controlled" (n = 17) and "uncontrolled" (n = 10), according to the consensus conference criteria (21), and in "partially controlled" (n = 14), when discordance among GH after the oral glucose tolerance test and basal IGF-I values was recorded (Table 1).

All patients and controls underwent a lactulose breath test (LH-BT) and completed a questionnaire to evaluate the presence of gastrointestinal symptoms (chronic diarrhea, both induced or spontaneous abdominal pain either in the upper or lower part, meteorism, flatulence, nausea, tenesmus, weight loss, constipation, and fever). After a 12-h fasting, H₂ breath concentration, in parts per million (ppm), was measured by gas chromatography at basal conditions and every 15 min for at least 4 h after the administration of an oral loading dose of lactulose (10 g in 120 ml of water). Alveolar air samples were collected in a 750-ml bag equip with a "T" with a nozzle, and connected to a bag for the collection of air coming from the respiratory dead space.

All subjects were studied after an overnight fast, having been instructed to avoid foods likely to generate H₂ for the 24 h before the test. The day preceding the examination, all the subjects had a preparation diet based on not seasoned boiled rice, meat cooked on a hot plate or boiled fish, and natural water. This meal was followed by a 12-h fasting period. Breath testing started between 0830 and 0930, after thorough mouth washing with 40 ml of 1% chlorhexidine solution. Smoking and physical exercise were not allowed for 1 h before and throughout the test. The test was considered positive for SIBO in the presence of two or more distinct peaks of H₂ excretion (>10 ppm compared with the basal value).

OCTT was defined as the time elapsing between lactulose ingestion and a sustained increase in H₂ excretion of 10 ppm above the baseline value, which is about 90 ± 15 min in normal subjects. Therefore, OCTT was calculated on the basis of the colic peak of H₂ excretion. The OCTT was not calculated, both in patients and controls, when the increment of H₂ excretion was not displayed during the test, and the parameter was not considered for the statistical analysis. LH-BT also evaluates the presence of bacterial overgrowth, which is defined by the presence of a peak(s) more than 10 ppm occurring before the colonic peak. Four exemplary profiles of H₂ excretion (peaks) during the LH-BT are shown in Fig. 1.

View larger version (15K): [in this window] [in a new window]   FIG. 1. SIBO and OCTT in acromegalic patients and controls. Four exemplary profiles obtained during the H2 LH-BT in a SIBO-negative control subject (top left), SIBO-positive control subject (top right), SIBO-negative acromegalic patient (bottom left), and SIBO-positive acromegalic patient (bottom right). The arrowheads show the normal H2 colic peak, which occurs about 90 ± 15 min after lactulose administration in normal subjects, whereas it appears about 170 ± 10 min in acromegalic patients. The arrows show the H2 precocious peaks, which indicate the presence of SIBO in both acromegalic patients and controls.

Assays

GH levels were determined in serum by a chemiluminescent ICMA assay (Immulite; Diagnostic Products Corp., Los Angeles, CA). The analytical sensitivity of this assay was 0.01 µg/liter, and the accuracy was less than 7% in the standard curve range; the standard curve was calibrated against the World Health Organization First Intramural Research Program 80/505 (1 mg = 2.6 IU). All these data have been validated in our laboratory.

IGF-I was measured by a RIA using immunochemicals and tracer provided by Biosource (Nivelles, Belgium). The sensitivity of the assay was 150 µg/liter (0.2 nmol/liter); the intraassay and interassay coefficients of variation were 6% and 7.5%, respectively.

To avoid interferences due to binding proteins, single-plasma EDTA samples were treated with ethanol, according to Daughaday et al. (22). IGF-I was measured in basal conditions, and it was reported as age-based SD scores, calculated on the basis of data obtained from over 4000 normal subjects of both sexes, from 0–100 yr, grouped into decades of age.

Statistical analysis

Statistical analysis of data was performed by the SPSS software, version 12 for Windows (SPSS, Inc., Chicago, IL). The analysis was performed using the Mann-Whitney U test for nonparametric data, both for the comparison between patients and controls and inside the single groups. A ² test was performed to evaluate SIBO prevalence in all the examined groups. The quantitative variables were expressed as mean ± SEM.

The evaluation of SIBO eradication was performed according to the analysis "intention to treat" (eradicated patients/patients who assumed the drug at least one time) and "for protocol" (eradicated patients/patients who completed the treatment).

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Prevalence of SIBO

This study demonstrated an increased prevalence of SIBO in acromegalic patients compared with controls (18 of 41, 1 of 30, respectively; P < 0.0001) (Fig. 2).

View larger version (8K): [in this window] [in a new window]   FIG. 2. Prevalence of SIBO in acromegalic patients and controls. Black bars indicate the patients were positive at the LH-BT. *, P < 0.0001 vs. controls.

OCTT

OCTT was significantly prolonged in the acromegalic patients when compared with healthy controls (169.53 ± 8.15 vs. 107.25 ± 6.56 min, respectively; P < 0.0001) (Fig. 3). There was a statistically significant difference in the OCTT between "treated" and "untreated" patients (183.21 ± 9.01 vs. 158.89 ± 6.38 min, respectively; P = 0.02), and between these two groups and healthy controls (105.75 ± 6.34 min; P < 0.0001) (Fig. 3). Conversely, there was not a significant difference in the OCTT among the "controlled," "uncontrolled," and "partially controlled" patients (Table 1). Moreover, analyzing OCTT values in "untreated" patients as function of the clinical control, there was no significant difference between the three groups: "untreated controlled" (154.44 ± 3.79 min), "untreated uncontrolled" (172.50 ± 2.74 min), and "untreated partially controlled" patients (160.71 ± 9.41 min) (Fig. 4).

View larger version (6K): [in this window] [in a new window]   FIG. 3. Box and whisker plots of OCTT values in patients "treated" with SSAs and patients "untreated" compared with controls. The lines in the boxes represent the median; the boxes are the 25th–75th percentile range, and the whiskers are the 10th–90th percentile range. Groups: 0, "untreated"; 1, "treated"; and 2, controls. *, P = 0.02. **, P < 0.0001.

View larger version (6K): [in this window] [in a new window]   FIG. 4. Box and whisker plots of OCTT values in acromegalic patients subdivided considering both the presence of medical therapy with SSAs and the disease control. Groups: 1, "untreated and controlled"; 2, "treated and controlled"; 3, "untreated and uncontrolled"; 4, "treated and uncontrolled"; 5, "untreated and partially controlled"; 6, "treated and partially controlled"; and 7, "controls."

Questionnaire results and treatment of SIBO

There were 13 SIBO-positive acromegalic patients who underwent antibiotic treatment. Of the five remaining SIBO-positive patients, two refused the eradicating therapy with rifaximin, and three missed the follow-up. Of the 13 treated patients, seven obtained eradication of the bacterial overgrowth at follow-up LH-BT ("for protocol" = 53.84%, "intention to treat" = 43.75%). The analysis of symptoms showed that patients affected by SIBO presented a trend toward an increased prevalence of intestinal meteorism (50%) and flatulence (50%) compared with unaffected patients (39.1% and 39%, respectively), however, without a significant statistical difference (Fig. 5). After eradication therapy, symptoms disappeared from 60% of the treated patients, whereas symptoms improved in the remaining patients. Only one patient referred the appearance of a mild cutaneous rush during treatment with rifaximine, but the therapy was completed.

View larger version (8K): [in this window] [in a new window]   FIG. 5. Prevalence of intestinal symptoms in SIBO-positive (black bars) and SIBO-negative (white bars) acromegalic patients.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

In our study six patients and eight controls did not show any H₂ excretion peak during the test, probably due to the presence of mainly methanogenic colic microbial populations in these subjects, in accordance with literature-reported data (24). Therefore, in these subjects considered SIBO-negative, it was unfeasible to calculate the OCTT. Moreover, in three SIBO-positive acromegalic patients, it was impossible to obtain an accurate calculation of the OCTT because of the presence of a partial fusion among the H₂ excretion peak due to the bacterial overgrowth and the peak due to the substrate fermentation in the cecum. Even if this drawback occurred, a statistically significant higher prevalence of SIBO was clearly demonstrated in acromegalic patients compared with controls. We also performed a statistical analysis dividing patients on the basis of the ongoing medical therapy and the disease control to understand better the possible causes of this high prevalence never described before. Indeed, SSAs have been reported to influence the OCTT. In fact, the sc administration of octreotide in normal subjects may induce the intestinal onset of motor complexes similar to those of phase III of the peristalsis but of major amplitude and duration. Moreover, octreotide delayed the OCTT, particularly by reducing antral motility and increasing gastric emptying time (4, 5). For this reason, octreotide was used in sclerodermic patients to promote intestinal bacterial clearance (6).

Our data also confirm that the long-acting formulation of SSAs may delay OCTT. Indeed, "treated" patients had a significant slower OCTT compared with "untreated" patients and healthy controls. Conversely, as far as SIBO presence is concerned, no difference between "treated" and "untreated" patients was shown. These data confirm the already known influence of SSAs on intestinal motility, suggesting, however, a neutral role of these drugs on SIBO pathogenesis.

Moreover, a significantly slower OCTT was present in "untreated" patients compared with healthy controls, suggesting that acromegaly per se may cause intestinal motility alterations. As far as the disease control is concerned, no significant differences were observed in the OCTT values among the three groups ("controlled," "uncontrolled," and "partially controlled"). This evidence suggests that these alterations can be irreversible and, when established, persisting, although patients have attained biochemical control of the disease. However, considering the small size of the groups, further studies on a larger population and using additional specific techniques to investigate the intestinal motility, such as manometry and radiological survey, are warranted.

Because this group of acromegalic patients did not display other predisposing factors for the development of an intestinal bacterial contamination, the prolonged OCTT and the high prevalence of SIBO may suggest an intrinsic motility alteration of the small intestine in these patients.

Since nonspecific gastrointestinal symptoms frequently occur in acromegaly, the prevalence and characteristics of these symptoms were evaluated, and a higher prevalence of meteorism and flatulence was observed in patients with positive LH-BT. In agreement with other studies (15), where malabsorption is reported as a rare complication of SIBO, this feature was not recorded in our patients, whereas irritable bowel syndrome-like intestinal symptoms were present. Moreover, because of the limited sensibility of the LH-BT, it is possible that the real number of patients affected by SIBO may be even higher. Indeed, although being LH-BT-negative, some patients referred intestinal symptoms in line with the presence of SIBO, suggesting that this alteration may significantly contribute to the occurrence of intestinal symptoms in acromegaly.

Rifaximin showed to be a useful primary level treatment in acromegalic patients affected by SIBO. Indeed, the antibiotic treatment was safe and effective in more than 50% of patients. Rifaximin, a nonabsorbable antibiotic belonging to the rifamycins family, determined an eradication rate in SIBO-positive acromegalic patients, consistent with the rate reported in literature in nonacromegalic subjects (25, 26). Moreover, 60% of treated patients referred a significant improvement of the symptoms. Further studies are needed to determine which is the best therapeutic approach in patients nonresponsive to a first cycle of treatment or with a recurrent disorder.

In conclusion, these data demonstrate, for the first time, that SIBO occurs more frequently in acromegalic patients than in normal subjects and that medical therapy with SSAs does not influence the presence of SIBO. A specific intestinal symptom in acromegalic patients can be caused by the presence of SIBO, however, therapy with rifaximin is safe and useful for the eradication of SIBO. Moreover, OCTT is significantly delayed in both "treated" and "untreated" acromegalic patients, suggesting that acromegaly may determine per se an impairment of the intestinal motility. Indeed, clinical control of acromegaly does not influence the altered bowel motility, suggesting delayed OCTT as another irreversible complication of acromegaly. Finally, the slower intestinal transit time may represent a risk factor for the development of SIBO.

These intestinal abnormalities in acromegaly might be related to the existence of an autonomic intestinal impairment, similar to that which we have previously demonstrated at the cardiovascular level (27).

	Footnotes

 
This work was supported by research grants from Fondo per gli Investimenti della Ricerca di Base (FIRB RBAU019TMF_001), Ministero dell’Università e della Ricerca Scientifica (2002067251-001), and an educational grant from the CARIGE Foundation (assegno di ricerca).

Disclosure Statement: The authors have nothing to declare.

First Published Online April 3, 2007

¹ E.R. and A.P. contributed equally.

Abbreviations: H₂, Hydrogen; LH-BT, lactulose breath test; OCTT, orocecal transit time; ppm, parts per million; SIBO, small intestinal bacterial overgrowth; SSA, somatostatin analog.

Received November 14, 2006.

Accepted March 27, 2007.

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Top Abstract Introduction Patients and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) All Versions of this Article: 92/6/2119    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Resmini, E. Articles by Ferone, D. Search for Related Content PubMed PubMed Citation Articles by Resmini, E. Articles by Ferone, D. Related Collections Endocrine Oncology Neuroendocrinology and Pituitary