Non-Celiac Enteropathies Dig Dis 2015;33:200–207 DOI: 10.1159/000371400
Motility Alterations in Celiac Disease and Non-Celiac Gluten Sensitivity Maria Ines Pinto-Sanchez Premysl Bercik Elena F. Verdu Farncombe Family Digestive Research Institute, Department of Medicine, McMaster University, Hamilton, Ont., Canada
Abstract Regulation of gut motility is complex and involves neuromuscular, immune and environmental mechanisms. It is well established that patients with celiac disease (CD) often display gut dysmotility. Studies have shown the presence of disturbed esophageal motility, altered gastric emptying, and dysmotility of the small intestine, gallbladder and colon in untreated CD. Most of these motor abnormalities resolve after a strict gluten-free diet, suggesting that mechanisms related to the inflammatory condition and disease process are responsible for the motor dysfunction. Motility abnormalities are also a hallmark of functional bowel disorders such as irritable bowel syndrome (IBS), where it has been proposed as underlying mechanism for symptom generation (diarrhea, constipation, bloating). Non-celiac gluten sensitivity (NCGS) is a poorly defined entity, mostly self-diagnosed, that presents clinically with IBS symptoms in the absence of specific celiac markers. Patients with NCGS are believed to react symptomatically to wheat components, and some studies have proposed the presence of low-grade inflammation in these patients. There is little information regarding the functional characterization of these patients before and after a gluten-free diet. A study suggested the pres-
© 2015 S. Karger AG, Basel 0257–2753/15/0332–0200$39.50/0 E-Mail [email protected] www.karger.com/ddi
ence of altered gastrointestinal transit in NCGS patients who also have a high prevalence of nonspecific anti-gliadin antibodies. Results of an ongoing clinical study in NCGS patients with positive anti-gliadin antibodies before and after a gluten-free diet will be discussed. Elucidating the mechanisms for symptom generation in NCGS patients is important to find new therapeutic alternatives to the burden of imposing a strict gluten-free diet in patients who do not have CD. © 2015 S. Karger AG, Basel
Introduction
Gut motility is the result of complex interactions between multiple systems operating at the level of the gut and systemically (fig. 1). As a consequence, alterations in gut motility will be present in a variety of inflammatory disorders (fig. 2). Gluten-related disorders involve all diseases triggered by gluten including celiac disease (CD) in its various manifestations, as well as the recently defined non-celiac gluten sensitivity (NCGS) [1–3]. CD is defined as a chronic small-intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals [4]. CD is one of the best well-characterized autoimmune diseases for which we have deep knowledge of the environmental, genetic, and immunoElena F. Verdu Farncombe Family Digestive Research Institute Department of Medicine, McMaster University Hamilton, ON L8S 4K1 (Canada) E-Mail verdue @ mcmaster.ca
Downloaded by: University of Hong Kong 147.8.31.43 - 5/9/2015 5:23:42 PM
Key Words Celiac disease · Gluten sensitivity · Motility
Immune system
CNS
ICCs
ENS
Muscle Food Bile acids Microbiota
logic factors involved [5]. Unlike CD, the definition of NCGS continues to be updated as new evidence arises, and there is no specific diagnostic test yet available. The latter precludes studies to accurately determine the real prevalence of NCGS, which has been estimated to be at least 6 times more frequent than CD [6]. However, this remains to be confirmed once its pathophysiology is better defined and biomarkers become available. Intestinal dysmotility occurs in a variety of disorders in which the gut has lost its ability to coordinate muscular activity because of endogenous or exogenous causes [7– 9]. Such disorders may be primary or secondary and may manifest symptomatically in a variety of ways, including abdominal distention, recurrent obstruction, abdominal colicky pain, constipation, gastroesophageal reflux disease and recurrent vomiting. In a broad sense, any alteration in the transit of foods and secretions into the digestive tract may be considered an intestinal motility disorder [10]. It is quite frequent to diagnose gastrointestinal motor abnormalities in celiac patients. Untreated celiacs can exhibit disturbed motility of the esophagus, stomach, small intestine, gallbladder, and colon. Not surprisingly, the data on motility in NCGS are just emerging. It is not the objective of this chapter to perform an in-depth review of the methods to study gut motility, which has been reviewed elsewhere in detail [11]. In the next section, we will briefly outline the main techniques used to measure gut motility in order to discuss the studies investigating this parameter in CD and, where possible, in NCGS. Motility in NCGS
GALT
Endocrine system
Food malabsorption Low-grade inflammation
Systemic inflammation Motility alterations in CD Dysfunction of the ANS
Hormonal derangements
Bile acid malabsorption
Fig. 2. Pathophysiological mechanisms involved in motility altera-
tions in CD. ANS = Autonomic nervous system.
Brief Overview of Methods to Assess Gut Motility
Several methods are available to investigate gut motility for clinical or research purposes. The choice of method will depend on the main objective (clinical vs. research) Dig Dis 2015;33:200–207 DOI: 10.1159/000371400
201
Downloaded by: University of Hong Kong 147.8.31.43 - 5/9/2015 5:23:42 PM
ity. Gut motility is the result of complex interactions between the different tissues in the gut [smooth muscle, enteric nervous system (ENS), gut-associated lymphoid tissue (GALT) and pacemaker cells in the gut, and the interstitial cells of Cajal (ICCs)]. The gut generates spontaneous electrical and contractile activity that is controlled by signals from the central nervous system (CNS), and the endocrine and systemic immune systems. These interactions are bidirectional. In addition to these, luminal factors coming from the food (e.g. dietary proteins such as gluten) and intestinal microbes have an important regulatory effect on gut immune and secretomotor activity in the host.
Color version available online
Fig. 1. Mechanisms that control gut motil-
Mouth-to-Cecum Transit Time: Lactulose H2 Breath Test After an overnight fast, subjects are requested to drink a lactulose-containing liquid/meal. After 30 min, breath hydrogen is measured to analyze 50-ml samples of end expiratory breath collected at 10-min intervals. A curve is drawn to show the hydrogen concentration. After a slight rise occurring in about 20 min, the breath hydrogen concentration normally falls and remains steady for a variable time, followed by a second rise steadily producing a sigmoid curve. The time to the first sustained rise (>10 parts per million above basal) in breath hydrogen concentration represents the mouth-to-cecum transit time (MCTT). The rate of rise of the breath hydrogen is usually assessed in ppm/min from the slope of the curve lying between 10 and 50% of the maximal rise in breath hydrogen [12]. Antroduodenal Manometry This constitutes a valuable method to assess gastroduodenal motility, and consists of the measurement of motor activity by the insertion of a manometric PVC catheter just beyond the angle of Treitz [13]. Intraluminal pressures are recorded using high-resolution solid-state transducers or water-perfused systems. The recordings are performed within fasting and postprandial periods. With this method, the three phases of interdigestive (fasting) motor activity, the migrating motor complex (MMC), can be identified. Phase I consists of motor quiescence, phase II of irregular contractile activity, and phase III (activity front) of regular contractile activity occurring at a frequency of 3 contractions per minute in the gastric antrum and contractions per minute in the duodenum-jejunum. Ultrasound Several approaches based on a duplex technique with serial determinations of cross-sectional areas or 3-dimensional ultrasonography with volume algorithms have been introduced to assess gastric emptying [14, 15]. Furthermore, transabdominal ultrasonography can be used 202
Dig Dis 2015;33:200–207 DOI: 10.1159/000371400
to measure transpyloric flow [14, 16]. Ultrasonography is easily accessible, noninvasive and does not expose the subject to radiation. The method is operator-dependent, reliable only for liquid meals and difficult to use in obese subjects [14]. Scintigraphy Two different isotopes can be used to measure gastric emptying by scintigraphy, a digestive solid marker and a liquid marker. 99Tc sulphur colloid radiolabelled scrambled egg is often used as a digestible solid component and indium-111 diethylenetriaminepentaacetic acid in water is used as a liquid marker. The scintigraphy approach also allows for the evaluation of small-intestinal and colonic motility [14]. 13C-Octanoid
Breath Test The 13C-octanoic acid breath test is frequently used to assess gastric emptying since it is not radioactive, it is accurate, and also safe for children [17]. Fatty acids labelled with the nonradioactive isotope 13C-octanoic acid can be used to measure gastric emptying as 13C is absorbed in the intestine and excreted by breath [14]. The method has the advantage that it is easy to perform and inexpensive. However, the absorption, distribution metabolism and excretion of markers require many steps that may lead to an ambiguous interpretation of results [14]. Videocapsule Endoscopy VCE has previously been proposed as a method to assess intestinal morphology in CD [18–21]. However, its use in motility assessment has been recently evaluated. Ciaccio et al. [22] developed a method to detect and quantify differences in small-intestinal motility in celiac patients compared to controls using VCE images. Instead of investigating specific image features, as in previous studies, they used dynamic estimates of wall motility for image classification and sought to characterize motility according to frame-to-frame changes in lumen shape [22]. However, the methodology still needs to be validated before widespread implementation. Colonic Transit Time: Radiopaque Markers Measurement of colon transit time is the most basic and primary tool in evaluating disorders of colonic motility. Several techniques for measuring colon transit time currently exist. The standard measurement of colon transit time has been performed using radiopaque marker test. The latter is the most widely used method. Pinto-Sanchez/Bercik/Verdu
Downloaded by: University of Hong Kong 147.8.31.43 - 5/9/2015 5:23:42 PM
and its availability. Overall, esophageal motility can be investigated with manometry; gastric emptying with scintigraphy, 13C-octanoic breath test and ultrasound; orocecal transit time with lactulose H2 breath test and more recently with videocapsule endoscopy (VCE). Measurement of colonic transit has been attempted with radiopaque markers, and gallbladder motility with scintigraphy.
Table 1. Summary of current studies on gut motility in CD First author, year
System
Subjects
Method
Findings
Bassotti, 1994
OCT
16 (9 adults and 7 children)
Manometry
CD adults but not children showed a greater frequency of migrating motor complexes vs. controls during fasting
Bai, 1995
OCT
55 (25 untreated, 15 treated CD and 15 controls)
Lactulose/BT SHAPE
OCT was significantly delayed and colonic transit accelerated in untreated patients
Usai, 1995
Esophagus
36 CD (14 active and 22 treated) and 144 controls
Manometry pH-metry
CD may display esophageal abnormalities in esophageal motility
Chiarioni, 1997
OCT
16 CD and 20 HV
Lactulose BT and urine
Mouth-to-cecum transit time was increased in CD vs. controls
D-xylose
Spiller, 1987
OCT
27 CD and 10 controls
Lactulose BT
Delayed mouth-cecum transit in patients with steatorrhea
Perri, 1987
Gastric
20 CD before and after treatment
Gastric emptying 13 C-octanoic acid BT
CD patients markedly delayed gastric emptying of solids, which normalized after gluten withdrawal (6 months)
Cucchiara, 1995
Gastric
14 untreated CD 4 treated CD and 8 controls
Manometry
CD shorter duration of activity fronts and reduction in PP antral motility index vs. controls; the previous disappeared after GFD
Usai, 1997
Esophagus and gastric
30 untreated CD
Manometry Gastric emptying Scintigraphy
Esophageal abnormalities present
Fraquelli, 1999
Gallbladder
10 CD before and after GFD and 10 HV
Ultrasonography
Elevated somatostatin with increased gallbladder fasting; decreased cholecystokinin secretion reduced gallbladder emptying; GFD reversed these abnormalities
Benini, 2001
Gastric
16 CD and 24 HV
Lactulose BT
Impairment of gastric emptying in CD which is at least partially reversible after GFD
Giorgetti, 2004
Autonomic
8 CD and 8 HV
PAS
Correlation between autonomic dysfunction and CD
Bassotti, 2008
Gastric
11 CD and 33 controls
Manometry
Abnormalities >80% CD even though they were treated
Rocco, 2008
Gastric
CD controls
Gastric emptying acid BT
Delayed gastric emptying in CD, not correlated with tissue ghrelin changes
13C-octanoic
Fenini, 2012
OCT
Ciaccio, 2012
OCT
19 CD untreated, 14 CD treated and 24 controls
Mouth-to-cecum transit M-CTT more prolonged in CD vs. controls and not reverted after GFD Videocapsule
Delayed intestinal but accelerated colonic transit?
This test is simple and inexpensive, produces minimum radiation exposure and is reliable and reproducible. However, it requires good compliance of the patient. Radiopaque markers are plastic beads or rings that are usually ingested in a capsule containing 20–50 markers. The most common capsule used is Sitzmarks® (Konsyl Pharmaceuticals, Fort Worth, Tex., USA). Several methods have been suggested including the single-capsule technique and the multiple-capsule technique. The multiple-capsule technique requires the ingestion of 1 capsule
a day for 3 days, followed by abdominal X-ray on day 4 and/or day 7 [23]. Interpretation is based on the identification of markers in 3 regions, namely the right, left and rectosigmoid regions. These are defined by bony landmarks and gaseous outlines as described by Kim and Rhee [23] and Arhan et al. [24]. Colon transit times in each segment and throughout the entire colon are calculated by multiplying the number of markers by 1.2 (or by 1.0 when using a capsule containing 24 markers) [24, 25].
Motility in NCGS
Dig Dis 2015;33:200–207 DOI: 10.1159/000371400
203
Downloaded by: University of Hong Kong 147.8.31.43 - 5/9/2015 5:23:42 PM
OCT = Orocecal transit time; HV = healthy volunteers; BT = breath test.
Using esophageal and gastrointestinal manometry, Usai et al. [26, 27] found esophageal motor abnormalities in 50% of patients with CD and gastrointestinal motility alterations in 75% of them. In a collaborative study involving two medical centers, we evaluated esophageal motility by using manometry and pH impedance in 12 CD and 7 non-celiac controls. Preliminary results from this study demonstrated motility alterations in 83% of CD patients [28]. No studies are yet available on esophageal motility alterations in NCGS population.
Gastrointestinal Motility Alterations in CD and NCGS
Gastrointestinal motility alterations have been extensively studied in celiac patients. More than 30 years ago, Spiller et al. [12] measured for the first time M-CTT of a lactulose-labelled liquid test meal in 27 CD patients and 10 healthy controls (HC) and gastric emptying of an indium DTPA-labelled liquid test meal in 11 CD patients and 6 HC. The authors demonstrated that patients with CD and fat malabsorption tend to have a delayed mouthcecum transit in spite of apparently normal gastric emptying and normal levels of insulin, GIP, CCC, neurotensin and PYY [12]. A delay in M-CTT in CD was also reported by Benini et al. [29]. Usai et al. [26] found gastrointestinal motility abnormalities in 75% of untreated CD patients assessed by manometry. CD patients displayed a shorter length of phase III of MMC as well as postprandial contractility in children with CD [30]. The same group performed a study in 11 untreated and 12 treated adult CD patients and demonstrated that more than 80% of untreated celiacs had discrete motor abnormalities of the upper gut, in both fasting and fed periods [31]. A recent study by Ciaccio et al. [22] evaluated motility by using VCE (Given® SB2) in 11 CD patients on a gluten-free diet (GFD) and in 10 control subjects. The authors sought to develop an automated and quantitative technique to directly characterize motility according to frame-to-frame changes in lumen shape [22]. The study revealed differences in motility in CD patients compared to controls. However, limitations related to the methodology were identified, suggesting that the results should be taken with caution [32]. Further studies are needed to validate this method and confirm its usefulness in the evaluation of celiac patients.
204
Dig Dis 2015;33:200–207 DOI: 10.1159/000371400
Gastric motility and emptying in CD have been reported to be normal [12, 33, 34] or delayed [17, 26, 29, 35]. The reason for the different findings could relate to different methods used to assess gastric emptying [17, 35]. No studies are so far available evaluating gastrointestinal motility in NCGS.
Colonic Motility Alterations in CD and NCGS
Bai et al. [36] performed a study evaluating colonic motility in 1995. The authors studied 25 patients with untreated CD, 15 treated patients and 15 HC. Transit of radiopaque makers (Metcalf method), a measure of total colonic transit, was significantly faster in untreated CD patients. The major finding was that this abnormal colonic behavior was principally due to a subpopulation of untreated patients with very fast transit times (
Motility Alterations in Celiac Disease and Non-Celiac Gluten Sensitivity Maria Ines Pinto-Sanchez Premysl Bercik Elena F. Verdu Farncombe Family Digestive Research Institute, Department of Medicine, McMaster University, Hamilton, Ont., Canada
Abstract Regulation of gut motility is complex and involves neuromuscular, immune and environmental mechanisms. It is well established that patients with celiac disease (CD) often display gut dysmotility. Studies have shown the presence of disturbed esophageal motility, altered gastric emptying, and dysmotility of the small intestine, gallbladder and colon in untreated CD. Most of these motor abnormalities resolve after a strict gluten-free diet, suggesting that mechanisms related to the inflammatory condition and disease process are responsible for the motor dysfunction. Motility abnormalities are also a hallmark of functional bowel disorders such as irritable bowel syndrome (IBS), where it has been proposed as underlying mechanism for symptom generation (diarrhea, constipation, bloating). Non-celiac gluten sensitivity (NCGS) is a poorly defined entity, mostly self-diagnosed, that presents clinically with IBS symptoms in the absence of specific celiac markers. Patients with NCGS are believed to react symptomatically to wheat components, and some studies have proposed the presence of low-grade inflammation in these patients. There is little information regarding the functional characterization of these patients before and after a gluten-free diet. A study suggested the pres-
© 2015 S. Karger AG, Basel 0257–2753/15/0332–0200$39.50/0 E-Mail [email protected] www.karger.com/ddi
ence of altered gastrointestinal transit in NCGS patients who also have a high prevalence of nonspecific anti-gliadin antibodies. Results of an ongoing clinical study in NCGS patients with positive anti-gliadin antibodies before and after a gluten-free diet will be discussed. Elucidating the mechanisms for symptom generation in NCGS patients is important to find new therapeutic alternatives to the burden of imposing a strict gluten-free diet in patients who do not have CD. © 2015 S. Karger AG, Basel
Introduction
Gut motility is the result of complex interactions between multiple systems operating at the level of the gut and systemically (fig. 1). As a consequence, alterations in gut motility will be present in a variety of inflammatory disorders (fig. 2). Gluten-related disorders involve all diseases triggered by gluten including celiac disease (CD) in its various manifestations, as well as the recently defined non-celiac gluten sensitivity (NCGS) [1–3]. CD is defined as a chronic small-intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals [4]. CD is one of the best well-characterized autoimmune diseases for which we have deep knowledge of the environmental, genetic, and immunoElena F. Verdu Farncombe Family Digestive Research Institute Department of Medicine, McMaster University Hamilton, ON L8S 4K1 (Canada) E-Mail verdue @ mcmaster.ca
Downloaded by: University of Hong Kong 147.8.31.43 - 5/9/2015 5:23:42 PM
Key Words Celiac disease · Gluten sensitivity · Motility
Immune system
CNS
ICCs
ENS
Muscle Food Bile acids Microbiota
logic factors involved [5]. Unlike CD, the definition of NCGS continues to be updated as new evidence arises, and there is no specific diagnostic test yet available. The latter precludes studies to accurately determine the real prevalence of NCGS, which has been estimated to be at least 6 times more frequent than CD [6]. However, this remains to be confirmed once its pathophysiology is better defined and biomarkers become available. Intestinal dysmotility occurs in a variety of disorders in which the gut has lost its ability to coordinate muscular activity because of endogenous or exogenous causes [7– 9]. Such disorders may be primary or secondary and may manifest symptomatically in a variety of ways, including abdominal distention, recurrent obstruction, abdominal colicky pain, constipation, gastroesophageal reflux disease and recurrent vomiting. In a broad sense, any alteration in the transit of foods and secretions into the digestive tract may be considered an intestinal motility disorder [10]. It is quite frequent to diagnose gastrointestinal motor abnormalities in celiac patients. Untreated celiacs can exhibit disturbed motility of the esophagus, stomach, small intestine, gallbladder, and colon. Not surprisingly, the data on motility in NCGS are just emerging. It is not the objective of this chapter to perform an in-depth review of the methods to study gut motility, which has been reviewed elsewhere in detail [11]. In the next section, we will briefly outline the main techniques used to measure gut motility in order to discuss the studies investigating this parameter in CD and, where possible, in NCGS. Motility in NCGS
GALT
Endocrine system
Food malabsorption Low-grade inflammation
Systemic inflammation Motility alterations in CD Dysfunction of the ANS
Hormonal derangements
Bile acid malabsorption
Fig. 2. Pathophysiological mechanisms involved in motility altera-
tions in CD. ANS = Autonomic nervous system.
Brief Overview of Methods to Assess Gut Motility
Several methods are available to investigate gut motility for clinical or research purposes. The choice of method will depend on the main objective (clinical vs. research) Dig Dis 2015;33:200–207 DOI: 10.1159/000371400
201
Downloaded by: University of Hong Kong 147.8.31.43 - 5/9/2015 5:23:42 PM
ity. Gut motility is the result of complex interactions between the different tissues in the gut [smooth muscle, enteric nervous system (ENS), gut-associated lymphoid tissue (GALT) and pacemaker cells in the gut, and the interstitial cells of Cajal (ICCs)]. The gut generates spontaneous electrical and contractile activity that is controlled by signals from the central nervous system (CNS), and the endocrine and systemic immune systems. These interactions are bidirectional. In addition to these, luminal factors coming from the food (e.g. dietary proteins such as gluten) and intestinal microbes have an important regulatory effect on gut immune and secretomotor activity in the host.
Color version available online
Fig. 1. Mechanisms that control gut motil-
Mouth-to-Cecum Transit Time: Lactulose H2 Breath Test After an overnight fast, subjects are requested to drink a lactulose-containing liquid/meal. After 30 min, breath hydrogen is measured to analyze 50-ml samples of end expiratory breath collected at 10-min intervals. A curve is drawn to show the hydrogen concentration. After a slight rise occurring in about 20 min, the breath hydrogen concentration normally falls and remains steady for a variable time, followed by a second rise steadily producing a sigmoid curve. The time to the first sustained rise (>10 parts per million above basal) in breath hydrogen concentration represents the mouth-to-cecum transit time (MCTT). The rate of rise of the breath hydrogen is usually assessed in ppm/min from the slope of the curve lying between 10 and 50% of the maximal rise in breath hydrogen [12]. Antroduodenal Manometry This constitutes a valuable method to assess gastroduodenal motility, and consists of the measurement of motor activity by the insertion of a manometric PVC catheter just beyond the angle of Treitz [13]. Intraluminal pressures are recorded using high-resolution solid-state transducers or water-perfused systems. The recordings are performed within fasting and postprandial periods. With this method, the three phases of interdigestive (fasting) motor activity, the migrating motor complex (MMC), can be identified. Phase I consists of motor quiescence, phase II of irregular contractile activity, and phase III (activity front) of regular contractile activity occurring at a frequency of 3 contractions per minute in the gastric antrum and contractions per minute in the duodenum-jejunum. Ultrasound Several approaches based on a duplex technique with serial determinations of cross-sectional areas or 3-dimensional ultrasonography with volume algorithms have been introduced to assess gastric emptying [14, 15]. Furthermore, transabdominal ultrasonography can be used 202
Dig Dis 2015;33:200–207 DOI: 10.1159/000371400
to measure transpyloric flow [14, 16]. Ultrasonography is easily accessible, noninvasive and does not expose the subject to radiation. The method is operator-dependent, reliable only for liquid meals and difficult to use in obese subjects [14]. Scintigraphy Two different isotopes can be used to measure gastric emptying by scintigraphy, a digestive solid marker and a liquid marker. 99Tc sulphur colloid radiolabelled scrambled egg is often used as a digestible solid component and indium-111 diethylenetriaminepentaacetic acid in water is used as a liquid marker. The scintigraphy approach also allows for the evaluation of small-intestinal and colonic motility [14]. 13C-Octanoid
Breath Test The 13C-octanoic acid breath test is frequently used to assess gastric emptying since it is not radioactive, it is accurate, and also safe for children [17]. Fatty acids labelled with the nonradioactive isotope 13C-octanoic acid can be used to measure gastric emptying as 13C is absorbed in the intestine and excreted by breath [14]. The method has the advantage that it is easy to perform and inexpensive. However, the absorption, distribution metabolism and excretion of markers require many steps that may lead to an ambiguous interpretation of results [14]. Videocapsule Endoscopy VCE has previously been proposed as a method to assess intestinal morphology in CD [18–21]. However, its use in motility assessment has been recently evaluated. Ciaccio et al. [22] developed a method to detect and quantify differences in small-intestinal motility in celiac patients compared to controls using VCE images. Instead of investigating specific image features, as in previous studies, they used dynamic estimates of wall motility for image classification and sought to characterize motility according to frame-to-frame changes in lumen shape [22]. However, the methodology still needs to be validated before widespread implementation. Colonic Transit Time: Radiopaque Markers Measurement of colon transit time is the most basic and primary tool in evaluating disorders of colonic motility. Several techniques for measuring colon transit time currently exist. The standard measurement of colon transit time has been performed using radiopaque marker test. The latter is the most widely used method. Pinto-Sanchez/Bercik/Verdu
Downloaded by: University of Hong Kong 147.8.31.43 - 5/9/2015 5:23:42 PM
and its availability. Overall, esophageal motility can be investigated with manometry; gastric emptying with scintigraphy, 13C-octanoic breath test and ultrasound; orocecal transit time with lactulose H2 breath test and more recently with videocapsule endoscopy (VCE). Measurement of colonic transit has been attempted with radiopaque markers, and gallbladder motility with scintigraphy.
Table 1. Summary of current studies on gut motility in CD First author, year
System
Subjects
Method
Findings
Bassotti, 1994
OCT
16 (9 adults and 7 children)
Manometry
CD adults but not children showed a greater frequency of migrating motor complexes vs. controls during fasting
Bai, 1995
OCT
55 (25 untreated, 15 treated CD and 15 controls)
Lactulose/BT SHAPE
OCT was significantly delayed and colonic transit accelerated in untreated patients
Usai, 1995
Esophagus
36 CD (14 active and 22 treated) and 144 controls
Manometry pH-metry
CD may display esophageal abnormalities in esophageal motility
Chiarioni, 1997
OCT
16 CD and 20 HV
Lactulose BT and urine
Mouth-to-cecum transit time was increased in CD vs. controls
D-xylose
Spiller, 1987
OCT
27 CD and 10 controls
Lactulose BT
Delayed mouth-cecum transit in patients with steatorrhea
Perri, 1987
Gastric
20 CD before and after treatment
Gastric emptying 13 C-octanoic acid BT
CD patients markedly delayed gastric emptying of solids, which normalized after gluten withdrawal (6 months)
Cucchiara, 1995
Gastric
14 untreated CD 4 treated CD and 8 controls
Manometry
CD shorter duration of activity fronts and reduction in PP antral motility index vs. controls; the previous disappeared after GFD
Usai, 1997
Esophagus and gastric
30 untreated CD
Manometry Gastric emptying Scintigraphy
Esophageal abnormalities present
Fraquelli, 1999
Gallbladder
10 CD before and after GFD and 10 HV
Ultrasonography
Elevated somatostatin with increased gallbladder fasting; decreased cholecystokinin secretion reduced gallbladder emptying; GFD reversed these abnormalities
Benini, 2001
Gastric
16 CD and 24 HV
Lactulose BT
Impairment of gastric emptying in CD which is at least partially reversible after GFD
Giorgetti, 2004
Autonomic
8 CD and 8 HV
PAS
Correlation between autonomic dysfunction and CD
Bassotti, 2008
Gastric
11 CD and 33 controls
Manometry
Abnormalities >80% CD even though they were treated
Rocco, 2008
Gastric
CD controls
Gastric emptying acid BT
Delayed gastric emptying in CD, not correlated with tissue ghrelin changes
13C-octanoic
Fenini, 2012
OCT
Ciaccio, 2012
OCT
19 CD untreated, 14 CD treated and 24 controls
Mouth-to-cecum transit M-CTT more prolonged in CD vs. controls and not reverted after GFD Videocapsule
Delayed intestinal but accelerated colonic transit?
This test is simple and inexpensive, produces minimum radiation exposure and is reliable and reproducible. However, it requires good compliance of the patient. Radiopaque markers are plastic beads or rings that are usually ingested in a capsule containing 20–50 markers. The most common capsule used is Sitzmarks® (Konsyl Pharmaceuticals, Fort Worth, Tex., USA). Several methods have been suggested including the single-capsule technique and the multiple-capsule technique. The multiple-capsule technique requires the ingestion of 1 capsule
a day for 3 days, followed by abdominal X-ray on day 4 and/or day 7 [23]. Interpretation is based on the identification of markers in 3 regions, namely the right, left and rectosigmoid regions. These are defined by bony landmarks and gaseous outlines as described by Kim and Rhee [23] and Arhan et al. [24]. Colon transit times in each segment and throughout the entire colon are calculated by multiplying the number of markers by 1.2 (or by 1.0 when using a capsule containing 24 markers) [24, 25].
Motility in NCGS
Dig Dis 2015;33:200–207 DOI: 10.1159/000371400
203
Downloaded by: University of Hong Kong 147.8.31.43 - 5/9/2015 5:23:42 PM
OCT = Orocecal transit time; HV = healthy volunteers; BT = breath test.
Using esophageal and gastrointestinal manometry, Usai et al. [26, 27] found esophageal motor abnormalities in 50% of patients with CD and gastrointestinal motility alterations in 75% of them. In a collaborative study involving two medical centers, we evaluated esophageal motility by using manometry and pH impedance in 12 CD and 7 non-celiac controls. Preliminary results from this study demonstrated motility alterations in 83% of CD patients [28]. No studies are yet available on esophageal motility alterations in NCGS population.
Gastrointestinal Motility Alterations in CD and NCGS
Gastrointestinal motility alterations have been extensively studied in celiac patients. More than 30 years ago, Spiller et al. [12] measured for the first time M-CTT of a lactulose-labelled liquid test meal in 27 CD patients and 10 healthy controls (HC) and gastric emptying of an indium DTPA-labelled liquid test meal in 11 CD patients and 6 HC. The authors demonstrated that patients with CD and fat malabsorption tend to have a delayed mouthcecum transit in spite of apparently normal gastric emptying and normal levels of insulin, GIP, CCC, neurotensin and PYY [12]. A delay in M-CTT in CD was also reported by Benini et al. [29]. Usai et al. [26] found gastrointestinal motility abnormalities in 75% of untreated CD patients assessed by manometry. CD patients displayed a shorter length of phase III of MMC as well as postprandial contractility in children with CD [30]. The same group performed a study in 11 untreated and 12 treated adult CD patients and demonstrated that more than 80% of untreated celiacs had discrete motor abnormalities of the upper gut, in both fasting and fed periods [31]. A recent study by Ciaccio et al. [22] evaluated motility by using VCE (Given® SB2) in 11 CD patients on a gluten-free diet (GFD) and in 10 control subjects. The authors sought to develop an automated and quantitative technique to directly characterize motility according to frame-to-frame changes in lumen shape [22]. The study revealed differences in motility in CD patients compared to controls. However, limitations related to the methodology were identified, suggesting that the results should be taken with caution [32]. Further studies are needed to validate this method and confirm its usefulness in the evaluation of celiac patients.
204
Dig Dis 2015;33:200–207 DOI: 10.1159/000371400
Gastric motility and emptying in CD have been reported to be normal [12, 33, 34] or delayed [17, 26, 29, 35]. The reason for the different findings could relate to different methods used to assess gastric emptying [17, 35]. No studies are so far available evaluating gastrointestinal motility in NCGS.
Colonic Motility Alterations in CD and NCGS
Bai et al. [36] performed a study evaluating colonic motility in 1995. The authors studied 25 patients with untreated CD, 15 treated patients and 15 HC. Transit of radiopaque makers (Metcalf method), a measure of total colonic transit, was significantly faster in untreated CD patients. The major finding was that this abnormal colonic behavior was principally due to a subpopulation of untreated patients with very fast transit times (
