Publications by authors named "Jutta Keller"

48 Publications

The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome.

J Cell Mol Med 2021 Jun 24. Epub 2021 Jun 24.

Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland.

Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS-C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow-up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS-C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.
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http://dx.doi.org/10.1111/jcmm.16736DOI Listing
June 2021

European guideline on indications, performance and clinical impact of C-breath tests in adult and pediatric patients: An EAGEN, ESNM, and ESPGHAN consensus, supported by EPC.

United European Gastroenterol J 2021 Jun 14;9(5):598-625. Epub 2021 Jun 14.

Division of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland.

Introduction: C-breath tests are valuable, noninvasive diagnostic tests that can be widely applied for the assessment of gastroenterological symptoms and diseases. Currently, the potential of these tests is compromised by a lack of standardization regarding performance and interpretation among expert centers.

Methods: This consensus-based clinical practice guideline defines the clinical indications, performance, and interpretation of C-breath tests in adult and pediatric patients. A balance between scientific evidence and clinical experience was achieved by a Delphi consensus that involved 43 experts from 18 European countries. Consensus on individual statements and recommendations was established if ≥ 80% of reviewers agreed and <10% disagreed.

Results: The guideline gives an overview over general methodology of C-breath testing and provides recommendations for the use of C-breath tests to diagnose Helicobacter pylori infection, measure gastric emptying time, and monitor pancreatic exocrine and liver function in adult and pediatric patients. Other potential applications of C-breath testing are summarized briefly. The recommendations specifically detail when and how individual C-breath tests should be performed including examples for well-established test protocols, patient preparation, and reporting of test results.

Conclusion: This clinical practice guideline should improve pan-European harmonization of diagnostic approaches to symptoms and disorders, which are very common in specialist and primary care gastroenterology practice, both in adult and pediatric patients. In addition, this guideline identifies areas of future clinical research involving the use of C-breath tests.
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http://dx.doi.org/10.1002/ueg2.12099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259225PMC
June 2021

C-gastric emptying breath tests: Clinical use in adults and children.

Neurogastroenterol Motil 2021 Jun 17;33(6):e14172. Epub 2021 May 17.

Department of Paediatric Gastroenterology, Hepatology and Nutrition, KidZ Health Castle UZ Brussel, Brussels, Belgium.

C-gastric emptying breath tests ( C-GEBT) are validated, reliable, and non-invasive tools for measurement of gastric emptying (GE) velocity of solids and liquids without radiation exposure or risk of toxicity. They are recommended and routinely used for clinical purposes in adult as well as pediatric patients and can be readily performed onsite or even at the patient's home. However, the underlying methodology is rather complex and test results can be influenced by dietary factors, physical activity, concurrent diseases, and medication. Moreover, epidemiological factors can influence gastric emptying as well as production and exhalation of CO , which is the ultimate metabolic product measured for all C-breath tests. Accordingly, in this issue of Neurogastroenterology & Motility, Kovacic et al. report performance of the C-Spirulina breath test in a large group of healthy children and show significant effects of gender, pubertal status, and body size on test results. The purpose of this mini-review is to evaluate the clinical use of C-GEBT in adults and children, exploring available protocols, analytical methods, and essential prerequisites for test performance, as well as the role of GE measurements in the light of the current discussion on relevance of delayed GE for symptom generation.
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http://dx.doi.org/10.1111/nmo.14172DOI Listing
June 2021

[Bile acid diarrhea, stepchild of chronic diarrhea - prevalence, diagnosis and treatment. Update 2021].

Z Gastroenterol 2021 Jun 25;59(6):580-591. Epub 2021 Feb 25.

Israelitisches Krankenhaus, Hamburg.

Bile acid diarrhea is one of the most frequently undiagnosed causes of chronic diarrhea. A variety of different pathophysiologic causes can underlie chronic diarrhea. Even after exclusion of the more frequent causes, up to 5 % of the population remains affected by unexplained chronic diarrhea. In up to 50 % within this cohort, bile acid diarrhea is the underlying cause.The various pathophysiologies leading to bile acid diarrhea are well characterized. In this way, bile acid diarrhea can be divided into primary, secondary and tertiary subtypes. Common to all causes is the increased amount of bile acids in the colon and in the faeces and the resulting secretory-osmotic diarrhea, in more severe forms in combination with steatorrhea. The diagnosis of bile acid diarrhea follows a clear algorithm which, in addition to the search for the cause and possibly a therapeutic trial, recognizes the 75SeHCAT test as the reference method for the detection of an increased loss of bile acids. In view of the chronic nature of the symptoms and the need for permanent, lifelong therapy, the use of a one-time, reliable diagnostic test is justified, though the test is currently only available at a few centers. In addition to the treatment of identifiable underlying diseases, the current treatment includes the use of drugs that bind bile acids, with additional nutritional recommendations and vitamin substitutions.The present review article summarizes the pathophysiology and importance of bile acid diarrhea and discusses the current approach towards diagnosis and treatment.
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http://dx.doi.org/10.1055/a-1378-9627DOI Listing
June 2021

DEVELOPMENT OF A MULTINATIONAL CLINICAL PRACTICE GUIDELINE: A PRACTICAL STRUCTURED PROCEDURE.

Dig Dis 2020 Aug 20. Epub 2020 Aug 20.

Introduction: The development of a clinical guideline is a challenging process. National and international organizations have established a variety of approaches, grading systems, evaluation scales and voting modes, however a practical description which illustrates all steps from starting the initiative to publication and dissemination of the guideline is usually not provided. We describe a structured guideline procedure that can be adjusted to the requirements of other multinational guidelines.

Methods: Clinical scientists with experience of organizing and contributing to guidelines initiated this guideline project. A balance between scientific evidence and clinical experience was achieved by involving European specialist societies and physicians from 18 European countries. For persons contributing to the guideline process, different levels of involvement were defined. The tasks were assigned to different groups of persons, which formed scientific institutions.

Results: We describe organizational structures and institutions, a stepwise approach to tasks, and illustrate the multistep guideline development procedure in a flowchart diagram that shows the workflow and the assigned responsibilities and provides further details for the execution of each step, including timelines. The process is split into 4 phases: Foundation, Preparation, Voting and Publication.

Discussion: This structured procedure can serve as a blueprint for future multinational initiatives and may also aid future attempts to standardize and harmonize the guideline development processes. Although the described structured procedure is for a diagnostic guideline, it may also be appropriate for therapeutic guidelines by adjusting the acceptance criteria for statements and recommendations.
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http://dx.doi.org/10.1159/000511007DOI Listing
August 2020

Pathophysiology and management of diabetic gastroenteropathy.

Therap Adv Gastroenterol 2019 17;12:1756284819852047. Epub 2019 Jun 17.

Mech-Sense, Department of Gastroenterology and Hepatology and Department of Clinical Medicine, Aalborg University Hospital, Denmark.

Polyneuropathy is a common complication to diabetes. Neuropathies within the enteric nervous system are associated with gastroenteropathy and marked symptoms that severely reduce quality of life. Symptoms are pleomorphic but include nausea, vomiting, dysphagia, dyspepsia, pain, bloating, diarrhoea, constipation and faecal incontinence. The aims of this review are fourfold. First, to provide a summary of the pathophysiology underlying diabetic gastroenteropathy. Secondly to give an overview of the diagnostic methods. Thirdly, to provide clinicians with a focussed overview of current and future methods for pharmacological and nonpharmacological treatment modalities. Pharmacological management is categorised according to symptoms arising from the upper or lower gut as well as sensory dysfunctions. Dietary management is central to improvement of symptoms and is discussed in detail, and neuromodulatory treatment modalities and other emerging management strategies for diabetic gastroenteropathy are discussed. Finally, we propose a diagnostic/investigation algorithm that can be used to support multidisciplinary management.
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http://dx.doi.org/10.1177/1756284819852047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580709PMC
June 2019

[Interpretation und performance of high-resolution esophageal manometry: Recommendations of the German Association of Neurogastroenterology and Motility (DGNM) and the German Association of Gastroenterology, Digestive and Metabolic Diseases (DGVS)].

Z Gastroenterol 2018 Nov 12;56(11):1378-1408. Epub 2018 Nov 12.

Medizinische Klinik und Poliklinik II, LMU, Campus Großhadern, München.

Esophageal manometry provides a detailed evaluation of esophageal contractility and, therefore, represents the reference method for diagnosis of esophageal motility disorders. Significance and clinical relevance have been further increased by implementation of high-resolution esophageal manometry (HRM), which reveals the functional anatomy of the esophagus in a visually-intuitive manner. The current 3 rd version of the international Chicago Classification (CC v3.0) gives standardized recommendations on performance and interpretation of HRM and serves as the basis for much of this expert consensus document. However, CC v3.0 gives only limited information with regards to the function of the lower and upper esophageal sphincters, the use of adjunctive tests including solid test meals and long-term ambulatory HRM measurements. In this expert consensus, we describe how to perform and interpret HRM on the basis of the CC v3.0 with additional recommendations based on the results of recent, high-quality clinical studies concerning the use of this technology to assess the causes of esophageal symptoms in a variety of clinical scenarios.
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http://dx.doi.org/10.1055/a-0713-0944DOI Listing
November 2018

What Is the Impact of High-Resolution Manometry in the Functional Diagnostic Workup of Gastroesophageal Reflux Disease?

Authors:
Jutta Keller

Visc Med 2018 Apr 12;34(2):101-108. Epub 2018 Apr 12.

Department of Internal Medicine, Israelitic Hospital, University of Hamburg, Hamburg, Germany.

International guidelines agree that high-resolution esophageal manometry (HRM) is an integral part of the diagnostic evaluation of patients with refractory reflux symptoms and should be performed before antireflux surgery. Its most important goal is to explore differential diagnoses, in particular major esophageal motility disturbances, that may be responsible for symptoms. HRM additionally provides insights into all relevant pathomechanisms of gastroesophageal reflux disease (GERD): It can reveal important information on the morphology and function of the esophagogastric junction (EGJ), the presence of a hiatus hernia, transient lower esophageal sphincter relaxations, and dysmotility of the esophageal body. To obtain this information, a 3-step hierarchical system has been proposed for the algorithmic characterization of esophageal motor function. The first step is to investigate the morphology and contractility of the EGJ, the second to monitor esophageal body motor patterns in response to water swallows, and the third to determine the contraction reserve in patients with abnormal esophageal motor function using provocation tests. Observations made with HRM can not only explain the cause of symptoms in GERD patients but may also have the potential to direct specific treatment.
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http://dx.doi.org/10.1159/000486883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5981626PMC
April 2018

Clinical measurement of gastrointestinal motility and function: who, when and which test?

Nat Rev Gastroenterol Hepatol 2018 09;15(9):568-579

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.

Symptoms related to abnormal gastrointestinal motility and function are common. Oropharyngeal and oesophageal dysphagia, heartburn, bloating, abdominal pain and alterations in bowel habits are among the most frequent reasons for seeking medical attention from internists or general practitioners and are also common reasons for referral to gastroenterologists and colorectal surgeons. However, the nonspecific nature of gastrointestinal symptoms, the absence of a definitive diagnosis on routine investigations (such as endoscopy, radiology or blood tests) and the lack of specific treatments make disease management challenging. Advances in technology have driven progress in the understanding of many of these conditions. This Review serves as an introduction to a series of Consensus Statements on the clinical measurements of gastrointestinal motility, function and sensitivity. A structured, evidence-based approach to the initial assessment and empirical treatment of patients presenting with gastrointestinal symptoms is discussed, followed by an outline of the contribution of modern physiological measurement on the management of patients in whom the cause of symptoms has not been identified with other tests. Discussions include the indications for and utility of high-resolution manometry, ambulatory pH-impedance monitoring, gastric emptying studies, breath tests and investigations of anorectal structure and function in day-to-day practice and clinical management.
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http://dx.doi.org/10.1038/s41575-018-0030-9DOI Listing
September 2018

Expert consensus document: Advances in the diagnosis and classification of gastric and intestinal motility disorders.

Nat Rev Gastroenterol Hepatol 2018 05 6;15(5):291-308. Epub 2018 Apr 6.

Mayo Clinic, 200 First Street SW, Rochester, MN 55902, USA.

Disturbances of gastric, intestinal and colonic motor and sensory functions affect a large proportion of the population worldwide, impair quality of life and cause considerable health-care costs. Assessment of gastrointestinal motility in these patients can serve to establish diagnosis and to guide therapy. Major advances in diagnostic techniques during the past 5-10 years have led to this update about indications for and selection and performance of currently available tests. As symptoms have poor concordance with gastrointestinal motor dysfunction, clinical motility testing is indicated in patients in whom there is no evidence of causative mucosal or structural diseases such as inflammatory or malignant disease. Transit tests using radiopaque markers, scintigraphy, breath tests and wireless motility capsules are noninvasive. Other tests of gastrointestinal contractility or sensation usually require intubation, typically represent second-line investigations limited to patients with severe symptoms and are performed at only specialized centres. This Consensus Statement details recommended tests as well as useful clinical alternatives for investigation of gastric, small bowel and colonic motility. The article provides recommendations on how to classify gastrointestinal motor disorders on the basis of test results and describes how test results guide treatment decisions.
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http://dx.doi.org/10.1038/nrgastro.2018.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646879PMC
May 2018

United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU).

United European Gastroenterol J 2017 03 16;5(2):153-199. Epub 2017 Jan 16.

Department of Gastroenterology and Hepatology, Erasmus Medical Centre in Rotterdam, The Netherlands.

Background: There have been substantial improvements in the management of chronic pancreatitis, leading to the publication of several national guidelines during recent years. In collaboration with United European Gastroenterology, the working group on 'Harmonizing diagnosis and treatment of chronic pancreatitis across Europe' (HaPanEU) developed these European guidelines using an evidence-based approach.

Methods: Twelve multidisciplinary review groups performed systematic literature reviews to answer 101 predefined clinical questions. Recommendations were graded using the Grading of Recommendations Assessment, Development and Evaluation system and the answers were assessed by the entire group in a Delphi process online. The review groups presented their recommendations during the 2015 annual meeting of United European Gastroenterology. At this one-day, interactive conference, relevant remarks were voiced and overall agreement on each recommendation was quantified using plenary voting (Test and Evaluation Directorate). After a final round of adjustments based on these comments, a draft version was sent out to external reviewers.

Results: The 101 recommendations covered 12 topics related to the clinical management of chronic pancreatitis: aetiology (working party (WP)1), diagnosis of chronic pancreatitis with imaging (WP2 and WP3), diagnosis of pancreatic exocrine insufficiency (WP4), surgery in chronic pancreatitis (WP5), medical therapy (WP6), endoscopic therapy (WP7), treatment of pancreatic pseudocysts (WP8), pancreatic pain (WP9), nutrition and malnutrition (WP10), diabetes mellitus (WP11) and the natural course of the disease and quality of life (WP12). Using the Grading of Recommendations Assessment, Development and Evaluation system, 70 of the 101 (70%) recommendations were rated as 'strong' and plenary voting revealed 'strong agreement' for 99 (98%) recommendations.

Conclusions: The 2016 HaPanEU/United European Gastroenterology guidelines provide evidence-based recommendations concerning key aspects of the medical and surgical management of chronic pancreatitis based on current available evidence. These recommendations should serve as a reference standard for existing management of the disease and as a guide for future clinical research.
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http://dx.doi.org/10.1177/2050640616684695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349368PMC
March 2017

Gastric emptying and disease activity in inflammatory bowel disease.

Eur J Clin Invest 2015 Dec 2;45(12):1234-42. Epub 2015 Nov 2.

Department of Internal Medicine, Israelitic Hospital, Hamburg, Germany.

Background: Gastric emptying (GE) is delayed in a subset of patients with inflammatory bowel disease (IBD). We have shown before that altered release of gastrointestinal hormones may contribute to GE disturbances, but overall effects of disease activity remain unclear. Thus, we aimed to evaluate GE in patients with IBD during active disease and following therapy.

Design: A total of 20 healthy subjects (HC) and 26 patients with IBD hospitalized because of an acute episode of their disease (Crohn's disease (CD) n = 13, ulcerative colitis (UC) n = 13) underwent a standardized (13) C-octanoic acid GE breath test (baseline test). Plasma glucose, cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) were measured periodically throughout the test. A total of 16 patients underwent a second GE test after 3-4 months of therapy.

Results: At baseline, nine patients with IBD had pathologically delayed GE half-time (T½ > 150 min) (P = 0·028 vs. HC). Moreover, T½ was significantly longer in the total group of patients with IBD than in HC (129 ± 12 min vs. 96 ± 7, P = 0·030). Postprandial GLP-1 responses were elevated in IBD (P = 0·002 vs. HC) and correlated with T½ (P = 0·05). Following therapy clinical activity indices and T½ were decreased in IBD (P ≤ 0·01 vs. baseline), and T½ no longer differed from HC (P > 0·5). Moreover, GLP-1 plasma levels decreased significantly (P = 0·031).

Conclusions: Higher disease activity in IBD is associated with prolonged GE and increased release of GLP-1. Following effective therapy, GE is accelerated and GLP-1 release decreases significantly. Thus, increased release of GLP-1 from the inflamed mucosa might contribute to GE disturbances in IBD.
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http://dx.doi.org/10.1111/eci.12542DOI Listing
December 2015

[Chronic upper abdominal pain: Diagnostic and therapeutic algorithm].

Dtsch Med Wochenschr 2015 May 13;140(10):718-22. Epub 2015 May 13.

Medizinische Klinik, Israelitisches Krankenhaus Hamburg.

Between 20% and 40% of the population have chronic or recurrent upper abdominal pain, frequently in combination with other dyspeptic symptoms. In about 50% of patients, who visit a doctor because of these complaints, symptoms are caused by an organic disease, whereas the other patients suffer from functional disturbances. Currently, the Rome III-criteria are established for diagnosis of functional dyspepsia. They request epigastric pain burning, bothersome postprandial fullness and/or early satiety and absence of structural disease that is likely to explain the symptoms. These criteria need to have been fulfilled for the previous 3 months with symptom onset at least 6 months before diagnosis. For exclusion of organic disease performance of an upper endoscopy is required. Some experts also recommend to investigate routine laboratory parameters and to perform an abdominal ultrasound investigation. Only in young patients who present with typical and moderate symptoms and have no alarm symptoms, probatory therapy without previous technical investigations and, thus, without final establishment of the diagnosis, may be considered. If they do not respond adequately within 4 weeks, these patients also have to undergo further diagnostic testing. Therapeutic options for functional dyspepsia are limited. They include the clear explanation of the diagnosis, consideration of factors that trigger or ameliorate symptoms and application of drugs such as certain herbal remedies, acid suppressing drugs and/or prokinetics.
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http://dx.doi.org/10.1055/s-0041-101692DOI Listing
May 2015

Simultaneous non-invasive measurement of liquid gastric emptying and small bowel transit by combined 13C-acetate and H2-lactulose breath test.

J Breath Res 2014 Nov 24;8(4):046007. Epub 2014 Nov 24.

Department of Internal Medicine, Israelitic Hospital, Hamburg, Germany.

The 13C-acetate breath test (13C-ABT) allows noninasive measurement of liquid gastric emptying time (LGET), the H2-lactulose breath (H2-LBT) measures orocecal transit time (OCTT). Because of different test principles, both tests can generally be combined. This would not only spare time and resources but may also deliver additional information on the integrated regulation of gastrointestinal motor functions. Our aim was to define an adequate test protocol and to generate normal values for the combined 13C-ABT/H2-LBT. Twenty two healthy volunteers participated (HV, 12 females, age: 26.5  ±  4.7 years, BMI: 22  ±  2.1 kgm(-2). Fasting subjects received 200 ml of an aequous solution containing 150 mg 13C-acetate and 10 g lactulose. Breath samples for H2 measurements were collected before ingestion of the test solution and afterwards at 5 min intervals for 180 min, for 13C measurements sampling intervals were prolonged to 15 min after the first hour. LGET was defined as time of maximal 13C-exhalation, OCTT as increase in H2 of ⩾ 20 ppm above basal. Small bowel transit time (SBTT) was calculated as the difference between OCTT and LGET. Mean [95% CI] values for LGET, OCTT and SBTT were 26 [23-30] min, 85 [68-102] min and 60 [44-76] min, respectively. Normal values for LGET and OCTT corresponded with published data. SBTT was not correlated with LGET (R2 = 0.019; p = 0.546). By contrast, there was a very tight and highly significant correlation between SBTT and OCTT (R2 = 0.933; p < 0.001). Multivariate linear regression analyses confirmed that age, sex and BMI had no significant effects on OCTT or SBTT while LGET was weakly correlated with BMI (R2 = 0.240; p = 0.021). In conclusion, the combined 13C-ABT/H2-LBT allows simultaneous measurement of LGET and OCTT as well as calculation of SBTT.
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http://dx.doi.org/10.1088/1752-7155/8/4/046007DOI Listing
November 2014

Sensitivity and specificity of an abbreviated (13)C-mixed triglyceride breath test for measurement of pancreatic exocrine function.

United European Gastroenterol J 2014 Aug;2(4):288-94

Department of Internal Medicine, Israelitic Hospital, University of Hamburg, Hamburg, Germany.

Background: A modified (13)C-mixed triglyceride breath test ((13)C -MTGT) detects moderate pancreatic exocrine insufficiency noninvasively and reliably, but it requires prolonged breath sampling (6 hours (hr)).

Objective: We aimed to investigate whether (13)C -MTGT can be abbreviated, to optimize clinical usability.

Methods: We analyzed the (13)C-MTGT of 200 consecutive patients, retrospectively. Cumulative 1-5 hr (13)C-exhalation values were compared with the standard parameter (6-hr cumulative (13)C-exhalation). We determined the sensitivity and specificity of shortened breath sampling periods, by comparison with the normal values from 10 healthy volunteers, whom also underwent a secretin test to quantitate pancreatic secretion. Moreover, we evaluated the influence of gastric emptying (GE), using a (13)C-octanoic acid breath test in a subset (N = 117).

Results: The 1-5 hr cumulative (13)C-exhalation tests correlated highly and significantly with the standard parameter (p < 0.0001). Sensitivity for detection of impaired lipolysis was high (≥77%), but the specificity was low (≥38%) for the early measurements. Both parameters were high after 4 hrs (88% and 94%, respectively) and 5 hrs (98% and 91%, respectively). Multivariate linear correlation analysis confirmed that GE strongly influenced early postprandial (13)C-exhalation during the (13)C-MTGT.

Conclusion: Shortening of the (13)C -MTGT from 6 to 4 hrs of duration was associated with similar diagnostic accuracy, yet increased clinical usability. The influence of GE on early postprandial results of the (13)C-MTGT precluded further abbreviation of the test.
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http://dx.doi.org/10.1177/2050640614542496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4114120PMC
August 2014

The Pathophysiology of Malabsorption.

Viszeralmedizin 2014 Jun;30(3):150-4

Department of Internal Medicine, Israelitic Hospital, University of Hamburg, Germany.

Physiological digestion and absorption of nutrients within the gastrointestinal tract requires a complex interaction between motor, secretory, digestive, and absorptive functions that is vulnerable to a multitude of potential disturbances which may lead to global or specific malabsorption syndromes. Potential pathomechanisms that are illustrated in this article include insufficient mechanical breakdown of harder food components due to chewing problems and/or decreased antral contractility, critical reduction of time for absorption in patients with markedly enhanced upper gastrointestinal transit (e.g. dumping syndrome), impaired digestion and absorption of nutrient components caused by reduced gastric acid secretion, pancreatic exocrine insufficiency or reduced biliary secretion, defects of the enteral mucosa with enzyme deficiencies (e.g. disaccharidases) or lack of specific carrier mechanisms (e.g. hexose or aminoacid transporters), and critical quantitative loss of intestinal mucosa in patients with short bowel syndrome.
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http://dx.doi.org/10.1159/000364794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513829PMC
June 2014

13C-mixed triglyceride breath test for evaluation of pancreatic exocrine function in diabetes mellitus.

Pancreas 2014 Aug;43(6):842-8

From the Department of Internal Medicine, Israelitic Hospital, University of Hamburg, Hamburg, Germany.

Objective: The clinical relevance of pancreatic exocrine insufficiency (PEI) in diabetic patients is unclear mostly because established function tests are invasive and expensive or lack sensitivity and specificity. A modified version of the noninvasive 13C-mixed triglyceride breath test (13C-MTGT) has recently been shown to detect moderate PEI reliably in patients with chronic pancreatitis. Its sensitivity and specificity in other patient groups are unknown. We therefore aimed to clarify the significance of this test for patients with diabetes mellitus (DM).

Methods: A secretin cerulein test and a modified 13C-MTGT were performed in 14 patients with DM (10 patients with type 1 DM) and 10 healthy volunteers.

Results: Secretin cerulein test showed significantly lower outputs of amylase, trypsin, and lipase in DM compared with healthy volunteers (P < 0.05). Likewise, 13C-MTGT showed significantly lower maximal and cumulative 13C-exhalation in DM (P < 0.005). Stimulated lipase output correlated with cumulative 13C-exhalation (P < 0.05). However, when compared with normal values, only 2 patients with diabetes had abnormally low lipase output, whereas cumulative 13C-exhalation was pathologically decreased in 8 patients, including those with decreased lipase output.

Conclusions: The noninvasive 13C-MTGT can detect mild to moderate PEI in DM. However, the specificity of the 13C-MTGT is low in these patients probably because nonpancreatic mechanisms contribute to decreased intestinal lipolysis.
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http://dx.doi.org/10.1097/MPA.0000000000000121DOI Listing
August 2014

Recent advances in capsule endoscopy: development of maneuverable capsules.

Expert Rev Gastroenterol Hepatol 2012 Sep;6(5):561-6

Department of Internal Medicine, University of Hamburg, Israelitic Hospital, Hamburg, Germany.

One important disadvantage of modern capsule endoscopy is its lack of maneuverability. Thus, clinically available systems depend on transportation by spontaneous gastrointestinal motility. Even in subjects with normal motility, transit time for different intestinal segments may vary considerably, and relevant segments may be passed too quickly. This probably explains why approximately 10% of all pathologies are overlooked during small bowel investigations. Moreover, without maneuverable capsule endoscopes, the large inner surface of the stomach cannot be investigated properly. The most advanced approaches, which try to develop maneuverable systems for targeted inspection of the GI tract, use magnetic fields for steering of a videocapsule with magnetic inclusions. With such systems, preliminary clinical studies have already been performed. Other projects try to develop biologically inspired steering mechanisms such as capsules that can move on legs or they use electrical stimulation of the intestinal wall in order to induce contractions for propulsion of the videocapsule.
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http://dx.doi.org/10.1586/egh.12.26DOI Listing
September 2012

Effect of exenatide on cholecystokinin-induced gallbladder emptying in fasting healthy subjects.

Regul Pept 2012 Nov 6;179(1-3):77-83. Epub 2012 Sep 6.

Israelitic Hospital, Academic Hospital University of Hamburg, Hamburg, Germany.

Exenatide is a glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes and has been shown to lower blood glucose through multiple mechanisms, including glucose-dependent insulin secretion, suppression of postprandial glucagon release and slowing of gastric emptying. The effects of exenatide on biliary motility are unknown. This study evaluated the effect of a single dose of exenatide on cholecystokinin (CCK)-induced gallbladder emptying. Healthy subjects participated in this randomized, 2-period, double-blind crossover study. Fasting subjects received a single subcutaneous injection of exenatide (10 μg) or placebo 60 min before CCK infusion. Gallbladder volume and ejection fraction (EF) were assessed by ultrasonography before, during, and after CCK infusion (0.003 μg/kg infused over 50 min at 2 mL/min). The diameters of the main pancreatic duct and common bile duct were measured sonographically at the same time points before, during, and following CCK infusion. Administration of exenatide did not affect pre-CCK infusion gallbladder volume or EF compared to placebo. During the CCK-infusion, the mean minimum gallbladder volume was similar for exenatide (13.68 mL) and placebo (11.05 mL) (least squares mean [LSM] difference of 2.62 mL; 95% confidence interval [CI], -0.53, 5.78), but the mean maximum EF was lower for exenatide (28.79%) versus placebo (46.13%) (LSM difference of -17.34%; 95% CI, -30.54, -4.13). Exenatide had no clinically significant effects on pancreatic or bile duct diameters. In conclusion, exenatide reduced CCK-induced gallbladder emptying compared with placebo in fasting healthy subjects.
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http://dx.doi.org/10.1016/j.regpep.2012.08.005DOI Listing
November 2012

Irritable bowel syndrome--the main recommendations.

Dtsch Arztebl Int 2011 Nov 4;108(44):751-60. Epub 2011 Nov 4.

Israelitisches Krankenhaus Medizinische Klinik, Hamburg, Germany.

Background: Irritable bowel syndrome is characterized by chronic abdominal symptoms and irregular bowel movements without any cause than can be revealed by routine diagnostic assessment. In recent years, its pathophysiology has come to be much better understood, and new therapeutic approaches have been developed. These advances were taken into consideration and assessed for their relevance to clinical practice in the framework of a new interdisciplinary S3 guideline.

Methods: A systematic search of the literature retrieved a total 5573 articles, from which 243 were selected on the basis of criteria relating to their form and content, individually assessed, and summarized in evidence tables. The recommendations formulated in this way were discussed in a Delphi procedure and a consensus conference, then accordingly modified and finalized.

Results: Variable symptom constellations are caused by disturbances of gastrointestinal regulation at multiple levels. The diagnosis of irritable bowel syndrome requires both chronic bowel symptoms that interfere with everyday life and the exclusion of relevant differential diagnoses. Its treatment is based on general therapeutic principles, dietary recommendations, psychological components, and symptomatic medication. Bulking agents, laxatives, spasmolytics, loperamide, and probiotic agents are recommended (with variable recommendation strengths), as are--for selected patients--antidepressants, 5-HT4 agonists, 5-HT3 antagonists, and topical antibiotics.

Conclusion: The first German S3 guideline on irritable bowel syndrome translates up-to-date scientific knowledge as represented in current publications into concrete recommendations for diagnosis and treatment in clinical practice. In the future, it is likely that further causative pathophysiological mechanisms will be discovered; this should lead, in turn, to the development of new, causally directed treatments, which will supplement or replace the traditional, purely symptomatic treatments that are still in use today.
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http://dx.doi.org/10.3238/arztebl.2011.0751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226958PMC
November 2011

Peroral endoscopic myotomy for the treatment of achalasia: a prospective single center study.

Am J Gastroenterol 2012 Mar 8;107(3):411-7. Epub 2011 Nov 8.

Department of Interdisciplinary Endoscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objectives: Endoscopic balloon dilatation and laparoscopic myotomy are established treatments for achalasia. Recently, a new endoscopic technique for complete myotomy was described. Herein, we report the results of the first prospective trial of peroral endoscopic myotomy (POEM) in Europe.

Methods: POEM was performed under general anesthesia in 16 patients (male:female (12:4), mean age 45 years, range 26-76). The primary outcome was symptom relief at 3 months, defined as an Eckhard score ≤3. Secondary outcomes were procedure-related adverse events, lower esophageal sphincter (LES) pressure on manometry, reflux symptoms, and medication use before and after POEM.

Results: A 3-month follow-up was completed for all patients. Treatment success (Eckhard score ≤3) was achieved in 94% of cases (mean score pre- vs. post-treatment (8.8 vs. 1.4); P<0.001). Mean LES pressure was 27.2 mm Hg pre-treatment and 11.8 mm Hg post-treatment (P<0.001). No patient developed symptoms of gastro-esophageal reflux after treatment, but one patient was found to have an erosive lesion (LA grade A) on follow-up esophagogastroduodenoscopy. No patient required medication with proton pump inhibitors or antacids after POEM.

Conclusions: POEM is a promising new treatment for achalasia resulting in short-term symptom relief in >90% of cases. Studies evaluating long-term efficacy and comparing POEM with established treatments have been initiated.
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http://dx.doi.org/10.1038/ajg.2011.388DOI Listing
March 2012

A modified ¹³C-mixed triglyceride breath test detects moderate pancreatic exocrine insufficiency.

Pancreas 2011 Nov;40(8):1201-5

Department of Internal Medicine, Israelitic Hospital in Hamburg, Academic Hospital of the University of Hamburg, Hamburg, Germany.

Objectives: The noninvasive ¹³C-mixed triglyceride breath test (¹³C-MTG-T) has been shown to diagnose severe pancreatic exocrine insufficiency reliably. We hypothesized that sensitivity of the test could be increased by strict limitation of physical activity, correction for gastric emptying velocity, and/or increased lipid dose.

Methods: In 10 healthy volunteers and 9 patients with suspected pancreatic disease, a secretin test, a modified ¹³C-MTG-T (250 mg ¹³C-MTG, 26 g fat, breath samples over 8 hours), and a ¹³C-octanoic acid gastric emptying test were performed. Subjects remained strictly seated during breath testing.

Results: Intravenously administered secretin 1 U/kg·h stimulated outputs of all enzymes significantly. Mean basal and stimulated enzyme outputs were similar in patients and healthy controls; however, compared with normal values, 5 patients and 1 control had moderately decreased lipase output. Cumulative 4-, 6-, and 8-hour ¹³C exhalation was significantly lower in patients than in controls. Sensitivity of ¹³C-MTG-T (6-h cumulative ¹³C exhalation <27% of dose) for detection of decreased lipase output was 100%; specificity was 92%. Gastric emptying parameters were similar in patients and controls, and correction for these did not improve accuracy of ¹³C-MTG-T.

Conclusions: The modified ¹³C-MTG-T detects moderate pancreatic exocrine insufficiency.
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http://dx.doi.org/10.1097/MPA.0b013e318220ad98DOI Listing
November 2011

Effects of systemic administration of a local anesthetic on pain in acute pancreatitis: a randomized clinical trial.

Pancreas 2011 Jul;40(5):673-9

Department of Internal Medicine, Israelitic Hospital, Hamburg, Germany.

Objectives: Intravenous local anesthetics may ameliorate pain and clinical course in patients with major abdominal surgery.

Aim: To investigate their effects in acute pancreatitis.

Methods: Forty-six consecutive patients with acute pancreatitis randomly received intravenous procaine (2 g/24 h) or placebo for 72 hours in a double-blind fashion. Pain severity (visual analog scale, 0-100), on-demand pain medication (metamizole and/or buprenorphine), and the clinical course were monitored every 24 hours.

Results: Data of 44 patients were subjected to intention-to-treat analysis. Although there were no differences between groups before treatment, procaine treatment was associated with a stronger decrease in pain compared with placebo (median visual analog scale decrement, -62 vs -39, P = 0.025). Moreover, there was a greater proportion of patients with adequate (≥ 67%) pain reduction (75% vs 43%, P = 0.018), less use of additional analgesics (P = 0.042), and overall analgesic superiority (P = 0.015). Compared with placebo, the proportion of patients hospitalized after 2 weeks was reduced by 80% after procaine treatment (P = 0.012).

Conclusions: These findings support the hypothesis that systemic administration of local anesthetics might improve pain and accelerate clinical recovery in acute pancreatitis.
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http://dx.doi.org/10.1097/MPA.0b013e318215ad38DOI Listing
July 2011

Inspection of the human stomach using remote-controlled capsule endoscopy: a feasibility study in healthy volunteers (with videos).

Gastrointest Endosc 2011 Jan 9;73(1):22-8. Epub 2010 Nov 9.

Israelitic Hospital, University of Hamburg, Hamburg, Germany.

Background: Remote control of capsule endoscopes might allow reliable inspection of the human stomach.

Objective: To assess the safety and efficacy of manipulation of a modified capsule endoscope with magnetic material (magnetic maneuverable capsule [MMC]) in the human stomach by using a handheld external magnet.

Design: Open clinical trial.

Setting: Academic hospital.

Patients: Ten healthy volunteers.

Interventions: Subjects swallowed the MMC and sherbet powder for gastric distention. An external magnetic paddle (EMP-2) was used to manipulate the MMC within the stomach. MMC responsiveness was evaluated on a screen showing the MMC film in real time.

Main Outcome Measurements: Safety and tolerability (questionnaire), gastric residence time of the MMC, its responsiveness to the EMP-2, area of gastric mucosa visualized.

Results: There were no adverse events. The MMC was always clearly attracted by the EMP-2 and responded to its movements. It remained in the stomach for 39 ± 24 minutes. In 7 subjects, both the cardia and the pylorus were inspected and 75% or more of the gastric mucosa was visualized (≥50% in all of the remaining subjects). A learning curve was clearly recognizable (identification of MMC localization, intended movements).

Limitations: Small amounts of fluid blocked the view of apical parts of the fundus; gastric distention was not sufficient to flatten all gastric folds.

Conclusions: Remote control of the MMC in the stomach of healthy volunteers using a handheld magnet is safe and feasible. Responsiveness of the MMC was excellent, and visualization of the gastric mucosa was good, although not yet complete, in the majority of subjects. The system appeared to be clinically valuable and should be developed further. (

Clinical Trial Registration Number: DE/CA05/2009031008.).
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http://dx.doi.org/10.1016/j.gie.2010.08.053DOI Listing
January 2011

Remote magnetic control of a wireless capsule endoscope in the esophagus is safe and feasible: results of a randomized, clinical trial in healthy volunteers.

Gastrointest Endosc 2010 Nov 19;72(5):941-6. Epub 2010 Sep 19.

Department of Internal Medicine, Israelitic Hospital, Academic Hospital, University of Hamburg, Germany.

Background: Remote control of esophageal capsule endoscopes could enhance diagnostic accuracy.

Objective: To assess the safety and efficacy of remote magnetic manipulation of a modified capsule endoscope (magnetic maneuverable capsule [MMC]; Given Imaging Ltd, Yoqneam, Israel) in the esophagus of healthy humans.

Design: Randomized, controlled trial.

Setting: Academic hospital.

Patients: This study involved 10 healthy volunteers.

Intervention: All participants swallowed a conventional capsule (ESO2; Given Imaging) and a capsule endoscope with magnetic material, the MMC, which is activated by a thermal switch, in random order (1 week apart). An external magnetic paddle (EMP; Given Imaging) was used to manipulate the MMC within the esophageal lumen. MMC responsiveness was evaluated on a screen showing the MMC film in real time.

Main Outcome Measurements: Safety and tolerability of the procedure (questionnaire), responsiveness of the MMC to the EMP, esophageal transit time, and visualization of the Z-line.

Results: No adverse events occurred apart from mild retrosternal pressure (n = 5). The ability to rotate the MMC around its longitudinal axis and to tilt it by defined movements of the EMP was clearly demonstrated in 9 volunteers. Esophageal transit time was highly variable for both capsules (MMC, 111-1514 seconds; ESO2, 47-1474 seconds), but the MMC stayed longer in the esophagus in 8 participants (P < .01). Visualization of the Z-line was more efficient with the ESO2 (inspection of 73% ± 18% of the circumference vs 33% ± 27%, P = .01).

Limitations: Magnetic forces were not strong enough to hold the MMC against peristalsis when the capsule approached the gastroesophageal junction.

Conclusion: Remote control of the MMC in the esophagus of healthy volunteers is safe and feasible, but higher magnetic forces may be needed.
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http://dx.doi.org/10.1016/j.gie.2010.06.053DOI Listing
November 2010

Mechanisms of gastric emptying disturbances in chronic and acute inflammation of the distal gastrointestinal tract.

Am J Physiol Gastrointest Liver Physiol 2009 Nov;297(5):G861-8

Israelitic Hospital, D-22297, Hamburg, Germany.

It is unclear why patients with inflammation of the distal bowel complain of symptoms referable to the upper gastrointestinal tract, specifically to gastric emptying (GE) disturbances. Thus we aimed to determine occurrence and putative pathomechanisms of gastric motor disorders in such patients. Thirteen healthy subjects (CON), 13 patients with Crohn's disease (CD), 10 with ulcerative colitis (UC), and 7 with diverticulitis (DIV) underwent a standardized (13)C-octanoic acid gastric emptying breath test. Plasma glucose, CCK, peptide YY, and glucagon-like peptide-1 (GLP-1) were measured periodically and correlated with GE parameters. Results were given in means +/- SD. Compared with CON, GE half time (T) was prolonged by 50% in CD (115 +/- 55 vs. 182 +/- 95 min, P = 0.037). Six CD, 2 DIV, and 2 UC patients had pathological T (>200 min). Postprandial plasma glucose was increased in all patients but was highest in DIV and correlated with T (r = 0.90, P = 0.006). In CD, mean postprandial CCK levels were increased threefold compared with CON (6.5 +/- 6.7 vs. 2.1 +/- 0.6 pmol/l, P = 0.027) and were correlated with T (r = 0.60, P = 0.041). Compared with CON, GLP-1 levels were increased in UC (25.1 +/- 5.2 vs. 33.5 +/- 13.0 pmol/l, P = 0.046) but markedly decreased in DIV (9.6 +/- 5.2 pmol/l, P < 0.0001). We concluded that a subset of patients with CD, UC, or DIV has delayed GE. GE disturbances are most pronounced in CD and might partly be caused by excessive CCK release. In DIV there might be a pathophysiological link between decreased GLP-1 release, postprandial hyperglycemia, and delayed GE. These explorative data encourage further studies in larger patient groups.
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http://dx.doi.org/10.1152/ajpgi.00145.2009DOI Listing
November 2009

Remote magnetic manipulation of a wireless capsule endoscope in the esophagus and stomach of humans (with videos).

Gastrointest Endosc 2010 Jun 24;71(7):1290-3. Epub 2010 Apr 24.

Department of BioSurgery and Surgical Technology, Imperial College and London University, 41 Willow Road, London, NW3 1TN United Kingdom.

Background: Remote manipulation of wireless capsule endoscopes might improve diagnostic accuracy and facilitate therapy.

Objective: To test a new capsule-manipulation system.

Setting: University hospital.

Design And Interventions: A first-in-human study tested a new magnetic maneuverable wireless capsule in a volunteer. A wireless capsule endoscope was modified to include neodymium-iron-boron magnets. The capsule's magnetic switch was replaced with a thermal one and turned on by placing it in hot water. One imager was removed from the PillCam colon-based capsule, and the available space was used to house the magnets. A handheld external magnet was used to manipulate this capsule in the esophagus and stomach. The capsule was initiated by placing it in a microg of hot water. The capsule was swallowed and observed in the esophagus and stomach by using a gastroscope. Capsule images were viewed on a real-time viewer.

Main Outcome Measurements: The capsule was manipulated in the esophagus for 10 minutes. It was easy to make the capsule turn somersaults and to angulate at the cardioesophageal junction. In the stomach, it was easy to move the capsule back from the pylorus to the cardioesophageal junction and hold/spin the capsule at any position in the stomach. The capsule in the esophagus and stomach did not cause discomfort.

Limitations: Magnetic force varies with the fourth power of distance.

Conclusions: This study suggests that remote manipulation of a capsule in the esophagus and stomach of a human is feasible and might enhance diagnostic endoscopy as well as enable therapeutic wireless capsule endoscopy.
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http://dx.doi.org/10.1016/j.gie.2010.01.064DOI Listing
June 2010

Diagnosis of fat malabsorption by breath tests: just a breeze?

Authors:
Jutta Keller

Digestion 2009 26;80(2):95-7. Epub 2009 Jun 26.

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http://dx.doi.org/10.1159/000219315DOI Listing
February 2010

Tests of pancreatic exocrine function - clinical significance in pancreatic and non-pancreatic disorders.

Best Pract Res Clin Gastroenterol 2009 ;23(3):425-39

Department of Medicine, Israelitisches Krankenhaus, Hamburg, Germany.

The pancreas functions as the main factory for digestive enzymes and therefore enables food utilisation. Pancreatic exocrine insufficiency, partial or complete loss of digestive enzyme synthesis, occurs primarily in disorders directly affecting pancreatic tissue integrity. However, other disorders of the gastrointestinal tract, such as coeliac disease, inflammatory bowel disease, Zollinger-Ellison syndrome or gastric resection can either mimic or cause pancreatic exocrine insufficiency. The overt clinical symptoms of pancreatic exocrine insufficiency are steatorrhoea and maldigestion, which frequently become apparent in advanced stages. Several direct and indirect function tests are available for assessment of pancreatic function but until today diagnosis of excretory insufficiency is difficult as in mild impairment clinically available function tests show limitations of diagnostic accuracy. This review focuses on diagnosis of pancreatic exocrine insufficiency in pancreatic and non-pancreatic disorders.
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http://dx.doi.org/10.1016/j.bpg.2009.02.013DOI Listing
August 2009

Intestinal and anorectal motility and functional disorders.

Best Pract Res Clin Gastroenterol 2009 ;23(3):407-23

Department of Internal Medicine, Israelitic Hospital, Hamburg, Germany.

Motility and functional disorders of the small intestine, the colon and the anorectum can induce or contribute to symptoms such as diarrhoea, constipation and abdominal pain and may impair nutrient absorption in severe cases. Acute affections of intestinal functions e.g. during gastrointestinal infections usually need no functional diagnostics but resolve spontaneously or with adequate therapy of the underlying disease. By contrast, chronic disturbances of small intestinal, colonic and anorectal motility and/or sensitivity are subject to gastrointestinal function tests. The role of these tests for diagnosis and therapeutic handling of severe intestinal dysmotility/chronic intestinal pseudo-obstruction, severe constipation, diarrhoea, fecal incontinence and irritable bowel syndrome will be discussed in this review that mainly focuses on adults.
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http://dx.doi.org/10.1016/j.bpg.2009.02.012DOI Listing
August 2009
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