Autonomic nervous system dysregulation in irritable bowel syndrome.

BACKGROUND: Autonomic nervous system (ANS) regulation may be altered in functional diseases, including irritable bowel syndrome (IBS), but published data are not clear to date. The aim of the study was to analyze ANS function in IBS subjects classified by Rome III criteria and healthy controls using standardized technique. METHODS: ANS activity was evaluated by autoregressive spectral analysis of RR interval and systolic arterial pressure variabilities, to obtain indices of sympatho-vagal modulation of the heart and of spontaneous cardiac baroreflex (α index). A symptom list was used to score 18 somatic complaints (score 0-180) (4SQ). Fatigue and stress were assessed through the use of a global scoring index (0-10). KEY RESULTS: We enrolled 41 IBS subjects (29 F, age 40 ± 2 years) and 42 healthy matched controls. Heart rate was higher in IBS than control subjects (69 ± 2 vs 61 ± 1; p < 0.001). The total variance of RR interval variability, and α index, were significantly lower in IBS compared to controls (1983.12 ± 384.64 ms(2) vs 4184.55 ± 649.59 ms(2) ; 18.1 ± 2 ms/mmHg vs 29 ± 3 ms/mmHg; p < 0.01). The α index results showed an inverse correlation with stress scores and somatic symptoms. CONCLUSIONS & INFERENCES: IBS subjects display a significant reduction in α index, an established marker of cardiac baroreflex. ANS dysfunction appears to be involved in the pathophysiology of IBS and its assessment may open new perspectives for clinical management of patients suffering from IBS.

[Gastroesophageal reflux disease: therapeutic features (Part II)]. / La malattia da reflusso gastro-esofageo: aspetti terapeutici (Parte II).

Gastroesophageal reflux disease (GERD) can be defined as a condition resulting from the reflux of stomach contents into the esophagus. Its pharmacological treatment is aimed at symptom relief, healing of erosions and ulcerations and prevention of relapses. Based on the pathophysiology, the ideal treatment is directed to enhance basal sphincter pressure or decrease the frequency of TLESR, restore esophageal "clearance", accelerate gastric emptying and highten mucosal resistance as well as reduce or inhibit gastric acid secretion. Most of these targets are currently achievable because the availability of different types of drugs, however the "ideal" pharmacologic treatment of GERD does not exist. Current remedies for GERD include life style changes along with a wide array of antisecretory drugs, such as antacids, H2-antagonists and proton pump inhibitors (PPI). Surgery, based on anti-reflux procedures, and endoscopic approaches may have a role in the management of patients with GERD.

Chronic intestinal pseudo-obstruction: manifestations, natural history and management.

Chronic intestinal pseudo-obstruction (CIPO) is a rare pathological condition characterized by a marked derangement of gut propulsive motility mimicking mechanical obstruction, in the absence of any lesion occluding the gut lumen. This disease is often associated with a disabling and potentially life-threatening complications and is still too often unrecognized even in referral centres. As a result, patients receive neither appropriate care nor recognition of their severe health condition. Medical and surgical therapies are often unsatisfactory and long-term outcome turns out to be poor in the vast majority of cases. This article focuses on the main clinical features, the management and long-term outcome of patients affected by CIPO, with particular emphasis on those aspects which remain a matter of debate.

[Gastroesophageal reflux disease: clinical and pathophysiological features (part I)]. / La malattia da reflusso gastro-esofageo: aspetti clinici e fisio- patologici (Parte I).

Gastroesophageal reflux disease (GERD) can be described as a clinical picture resulting from the reflux of stomach contents into the esophagus. The actual prevalence of GERD remains unestablished, although this disorder is generally common in old patients, male sex and in subsets of patients with pulmonary manifestations such as asthma. From a pathophysiological stand-point, GERD is thought to have a multifactorial etiology which involves genetics, anatomical, functional, environmental, hormonal and pharmacological factors. GERD has different clinical presentations which may be divided in three main classes: typical symptoms (heartburn and regurgitation); atypical or extraesophageal symptoms (angina-like chest pain, asthma, chronic cough and laryngitis); and complications (ulcers, strictures and Barrett's esophagus). In GERD diagnosis a key role is played by: accurate symptom evaluation, response to proton pump inhibitors and, finally, at least one in a life-time endoscopy. Moreover, barium swallow X-ray, 24-h esophageal pH monitoring and gastro-esophageal manometry can be useful to support diagnosis in some unusual cases or in cases partially or unresponsive to standard pharmacologic treatment.

Gastro-oesophageal reflux and interstitial lung disease.

BACKGROUND: Interstitial lung disease is a heterogeneous entity, which encompasses a large number of pulmonary disorders, including idiopathic pulmonary fibrosis. Gastro-oesophageal reflux appears to be more prevalent in idiopathic pulmonary fibrosis than in controls and in patients with secondary pulmonary fibrosis, but its contribution to interstitial lung disease remains unsettled. AIMS: To prospectively evaluate gastro-oesophageal reflux in patients with interstitial lung disease and to define acid reflux patterns in patients with idiopathic and secondary forms of pulmonary fibrosis. MATERIALS AND METHODS: Twenty-eight patients (15M, median age 66 years, interquartile range 60-71) were studied by history taking, pulmonary function tests, high resolution computed tomography, oesophageal manometry and 24h oesophago-gastric pH monitoring. RESULTS: Sixteen patients (57%) had typical reflux symptoms. All patients completed 24h pH metry and 14 underwent oesophageal manometry. An abnormal oesophageal acid exposure was observed in 19 patients (68%), 13 of which complained of predominant typical reflux symptoms. A diagnosis of idiopathic pulmonary fibrosis was made in 18 patients, while the remaining 10 patients were classified as secondary pulmonary fibrosis. Secondary pulmonary fibrosis patients had more restrictive lung defect, as expressed as Tiffeneau index (p<0.05) and greater acid reflux at nighttime (p<0.05) than idiopathic pulmonary fibrosis patients. CONCLUSIONS: The prevalence of abnormal acid reflux in interstitial lung disease patients is high and, in particular, patients with secondary pulmonary fibrosis show higher oesophageal acid exposure than those with idiopathic form.

Idiopathic achalasia is not allelic to alacrima achalasia adrenal insufficiency syndrome at the ALADIN locus.

BACKGROUND: Evidence indicates that patients with familial achalasia associated with Allgrove or triple-A syndrome (i.e. alacrima, achalasia and adrenocorticotropin-resistant adrenal insufficiency with neurological impairment) have mutations of the alacrima achalasia adrenal insufficiency syndrome (AAAS) gene. AIM: The present study was aimed at identifying possible AAAS gene mutations in patients with established idiopathic non-familial achalasia. METHODS: Genomic DNA of 41 patients was isolated from peripheral blood cells using standard methods. The 16 exons of the AAAS gene (or ALADIN) were screened for mutations using the denaturing high-performance liquid chromatography method. RESULTS: Four heterozygous nucleotidic variations have been identified in patients with idiopathic achalasia, among which three were exonic conservative polymorphisms [i.e. D138D (GAT-->GAC), L227L (TTG-->CTG) and F285F (TTC-->TTT) in exons 5, 7 and 9, respectively]. The fourth nucleotidic variation was located in intron 13 (IVS14-23delT). All variants have been regarded as polymorphisms resulting in a normal ALADIN protein since they are either conservative or lying outside the consensus splice sites. CONCLUSIONS: Our data do not support a pathogenetic role for common AAAS gene mutations in patients with idiopathic achalasia as seen in Allgrove syndrome. These findings suggest the participation of different mechanisms in the pathogenesis of idiopathic achalasia.

Diagnosis and therapy of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is one of the most common gut functional diseases, affecting 10-20% of people worldwide. Although most patients do not seek medical help, the disease accounts for huge costs for both patients and health-care systems and worsens significantly patients' quality of life. Diagnosis is based on the identification of symptoms according to Manning, Rome I and Rome II criteria and exclusion of alarm indicators. IBS symptoms overlap with those of coeliac disease, lactose intolerance, food allergies and bile salt malabsorption. The treatment of IBS is centred on an excellent doctor-patient relationship along with drugs targeting the predominant symptom, especially during exacerbations. Current pharmacological remedies are unsatisfactory due to the high number of patients complaining of lack of response and/or symptom recurrence. Although useful in some IBS patients, the validity of psychotherapy deserves further investigation. A wide array of potentially useful drugs are currently under consideration in pre-clinical trials. A better understanding of the pathogenetic mechanisms underlying IBS may help to develop more effective drugs for this disease.

New pathophysiological mechanisms in irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a functional, multifactorial disease characterized by abdominal pain and erratic bowel habit. Changes in gastrointestinal motor function, enhanced perception of stimuli arising from the gut wall and psychosocial factors are thought to be major contributors for symptom generation. In recent years, several additional factors have been identified and postulated to interact with these classical mechanisms. Reduced ability to expel intestinal gas with consequent gas trapping and bowel distension may contribute to abdominal discomfort/pain and bloating. Abnormal activation of certain brain regions following painful stimulation of the rectum suggests altered processing of afferent signals. An acute gastrointestinal infection is now a recognized aetiological factor for symptom development in a subset of IBS patients (i.e. post-infectious IBS), who are probably unable to down-regulate the initial inflammatory stimulus efficiently. Furthermore, low-grade inflammatory infiltration and activation of mast cells in proximity to nerves in the colonic mucosa may also participate in the frequency and severity of perceived abdominal pain in post-infectious and non-specific IBS. Initial evidence suggests the existence of changes in gut microflora, serotonin metabolism and a genetic contribution in IBS pathophysiology. These novel mechanisms may aid a better understanding of the complex pathophysiology of IBS and to develop new therapies.

Upper gastrointestinal bleeding due to duodenal metastasis from primary lung carcinoma.

Metastatic dissemination of lung carcinoma may involve virtually all organs, however, symptomatic spread to the small bowel is a rare occurrence. Herein, we report a case of duodenal metastatic involvement leading to severe upper gastrointestinal bleeding in the absence of symptoms referable to the primary tumour.

Review article: Helicobacter pylori, mucosal inflammation and symptom perception--new insights into an old hypothesis.

The role of Helicobacter pylori and the accompanying mucosal inflammatory response in functional dyspepsia is still undefined. Human and animal studies have clearly demonstrated a link between intestinal mucosal inflammation and changes in sensory-motor function. Growing clinical and basic evidence supports the concept that a similar paradigm may occur in H. pylori-related dyspepsia. The infection may both induce gastric dysmotility and trigger neuroplastic changes in the afferent neural pathways leading to visceral hyperalgesia. A reduction of central antinociceptive control systems may also play a pathophysiological role. H. pylori eradication has provided disappointing results in terms of improvement of symptoms. This may reflect the long-term recovery of neuroplastic changes occurring in the afferent nervous system or, alternatively, the incomplete resolution of gastritis and the persistent production of inflammatory mediators by resident cells in the muscularis externa. The identification of these mechanisms may provide a better understanding of the pathophysiology of H. pylori-related dyspepsia and prompt innovative therapeutic approaches.

Rectal compliance, capacity, and rectoanal sensation in fecal incontinence.

OBJECTIVE: Assessments of the pathophysiology of fecal incontinence are skewed toward anal sphincter function; however, rectal compliance, rectoanal sensation and capacity may also be relevant. The aim of this study was to evaluate the usual and some novel diagnostic approaches in fecal incontinence. METHODS: In 22 unselected patients with fecal incontinence (21 F, 33-75 yr), we quantified: 1) symptoms, anorectal manometry, and anal ultrasound; 2) anal perception of temperature and light touch; 3) rectal sensitivity and compliance to distension; and 4) rectal reservoir function. Control values were obtained from two groups of 11 (seven F, 32-53 yr), and 32 (18 F, 19-44 yr) volunteers. RESULTS: Patients had urge (14), passive (four), or combined (four) fecal incontinence; symptoms were mild in three, moderate in nine, and severe in 10 patients. Most had low sphincteric pressures and ultrasonic abnormalities. Temperature perception was impaired (p < 0.05) in incontinent patients, to a greater extent in the proximal anal canal and in patients with passive, as opposed to urge, incontinence. Intraluminal pressures for sensations of rectal distension were lower in incontinent patients (p = 0.02). Artificial stools elicited sensations of rectal filling at lower volumes than did a barostat bag, and in patients with urge, as opposed to passive, incontinence. In patients and controls, the sensation of urgency was associated (r2 = 0.2, p < 0.01) with rectal compliance. CONCLUSIONS: We confirm that temperature sensation is impaired, and perception of rectal distension is not always reduced in fecal incontinence. Artificial stool tended to induce sensations at lower volumes than did balloon inflation. Altered sensory mechanisms may contribute to the pathophysiology of fecal incontinence.

Clinical use of manometry for the diagnosis of intestinal motor abnormalities.

Digestive symptoms suggestive of intestinal motor disorders, such as abdominal pain and distension, fullness, vomiting, constipation and diarrhoea, are very common and non-specific, and may be clinical manifestations of both organic and functional diseases. Both radiology and endoscopy are important in the diagnosis of structural gastrointestinal lesions that can affect motility and offer indirect signs of impaired gastrointestinal functions, but the diagnosis of gut motility disorders currently relies on the manometric assessment of contractile activities. Small bowel manometry helps to identify normal motility features and consequently to identify abnormal motor patterns. Small bowel manometry can help to differentiate mechanical obstruction from pseudo-obstruction and neurogenic from myogenic motor disorders. Manometry is an invasive technique which is not well accepted by patients and requires specific skills from investigators. Also, manometric assessment is limited to referral centres with a specific interest in the field of digestive functions, in general, and motility, in particular. Only patients who remain undiagnosed after extensive traditional work-up and fail repeated courses with medical therapy should be referred for the manometric test. Understanding the underlying pathophysiologic mechanisms of abnormal motility and developing new therapies are the goals of the current research in this fascinating field of medicine.

Review article: the continuing dilemma of dyspepsia.

Dyspepsia drains a substantial proportion of healthcare resources in industrialized countries and an appropriate management strategy is needed. An aetiological role for Helicobacter pylori infection has been demonstrated in a number of pathological conditions associated with dyspepsia, such as peptic ulcer and gastric malignancies, but not in functional dyspepsia. Endoscopy and diagnosis-based treatment, H. pylori testing and eradication therapy, history taking and empirical therapy, are the main tools that are currently available for managing patients with upper gastrointestinal symptoms. Endoscopy identifies malignancies and organic diseases of the proximal gut and therefore provides reassurance to both doctors and patients. It should be recommended in older patients with suspicious symptoms and it has proven to be more cost-effective than empirical H2-receptor antagonists in patients with ulcer-like symptoms. Empirical eradication in all dyspeptics without suspicious symptoms is a cost-effective approach that cures the majority of peptic ulcers. Nevertheless, it does not control symptoms in the majority of patients, it may exacerbate gastro-oesophageal reflux disease, and it encourages antibiotic resistance. The realities of current clinical practice require empirical therapy in most, if not all, the dyspeptics seen by general practitioners. A detailed history taking can help to diagnose gastro-oesophageal reflux disease and to identify suspicious symptoms. Furthermore, identification of dyspepsia subgroups may provide guidance for empirical therapy. Nevertheless, even analysis of individual symptoms does not provide a sufficient diagnostic yield to differentiate functional from organic dyspepsia and appropriate investigations are needed in patients with poor response to short-term therapy or frequent relapses.

Role of antibiotic therapy on long-term germ excretion in faeces and digestive symptoms after Salmonella infection.

BACKGROUND: The role of antibiotic therapy on Salmonella faecal excretion is controversial. Acute Salmonella gastroenteritis induces long-lasting digestive symptoms in up to one-third of subjects. The role of antimicrobial therapy on persistent post-infectious symptoms is unknown. AIM: To investigate the role of antibiotic therapy on long-term germ faecal excretion and digestive symptoms after Salmonella infection. SUBJECTS AND METHODS: 1543 subjects [518 aged between 3 and 5 years (35.3%); 950 between 6 and 10 years (64.7%) and 75 adults (4.9%)] involved in a single outbreak of Salmonella enteritis fulfilled the study criteria by repeating stool cultures and answering a symptom questionnaire 3 months post-infection. RESULTS: 327 subjects (21.2%) were treated with antibiotics during the acute infection [121 children aged 3-5 years (23.4%), 175 children aged 6-10 years (18.4%) and 31 adults (41.3%)]. Antibiotic treatment did not affect Salmonella excretion at any of the time points studied up to three months post-infection in any age group as compared to age-matched untreated controls. Persistent digestive symptoms were more common among the patients treated with antibiotics (9.5% vs. 2.9%; P=0.003). CONCLUSIONS: Antibiotic therapy does not affect Salmonella enteritis excretion. Digestive symptoms after clearance of the infectious agent are significantly higher in patients treated with antibiotics during acute gastroenteritis.

Idiopathic myenteric ganglionitis underlying intractable vomiting in a young adult.

Inflammatory infiltration of intestinal myenteric plexuses (i.e. myenteric ganglionitis), along with severe intestinal motor abnormalities, may accompany paraneoplastic syndromes, neurological disorders and gastrointestinal infections, although rare cases can be idiopathic. In this report, we describe the case of a patient who presented with chronic intractable vomiting and weight loss associated with idiopathic myenteric ganglionitis mainly involving the stomach. Tissue analysis showed that the inflammatory infiltrate comprised T lymphocytes (CD4+ and CD8+), and peptide immunolabelling revealed a marked decrease of substance P/tachykinin immunoreactive staining in nerve fibres and myenteric neurones. Following systemic steroid therapy, the patient's symptoms dramatically improved, and after one year of follow-up his general condition remains satisfactory. The possible mechanisms leading to symptom generation and gastric dysmotility in the context of an idiopathic myenteric ganglionitis are discussed.

Gastric emptying and dyspeptic symptoms in patients with nonautoimmune fundic atrophic gastritis.

Our aim was to evaluate the relationship between gastric emptying and demographic, clinical, histological, and secretory features in patients with nonautoimmune fundic atrophic gastritis. Only 31% of 45 patients with fundic atrophic gastritis presented with achlorhydria. Scintigraphic gastric emptying of solids was delayed compared to healthy controls. Patients with achlorhydria showed gastric emptying rates lower than those with preserved acid secretion. Significant, but weak, correlations were observed between emptying rates and both peak acid output (Rs = 0.33) and serum gastrin levels (Rs = -0.36), but not with grading of mucosal atrophy. No symptom differences were observed between patients with or without achlorhydria, but a weak correlation was detected between peak acid output and the severity of epigastric pain (Rs = 0.40). In conclusion, patients with fundic atrophic gastritis present delayed gastric emptying that is weakly related to the reduction of the acid secretion and the raising of serum gastrin levels rather than to the severity of the atrophy.

Esophageal and gastric nitric oxide synthesizing innervation in primary achalasia.

OBJECTIVE: We performed a qualitative and quantitative analysis of the nitrinergic neurons in the esophageal and gastric component of the lower esophageal sphincter (LES) and gastric fundus of patients with primary achalasia. METHODS: Four muscle strips were obtained from the esophagogastric junction (two from the esophageal and two from the gastric side of the LES), and two from the gastric fundus of six patients with endstage achalasia who underwent an esophagogastric myotomy plus hemifundoplication. Control specimens were obtained from eight patients who underwent surgery for cancer of the thoracic esophagus. Fixed sections were processed for NADPH-diaphorase histochemistry and the number (mean +/- SE) of nitrinergic neurons per section was visually quantified in each specimen. RESULTS: In the controls, nitric oxide fibers were distributed to the muscle layer and surrounding myenteric neurons of both the LES and the gastric fundus. By contrast, achalasic patients showed a marked decrease of nitric oxide nerves and labeled neurons in both esophageal and gastric components of the LES and the gastric fundus. Quantitative assessment in achalasic patients showed that the mean number of nitrinergic neurons was dramatically reduced in both the esophageal (0.2 +/- 0.1) and the gastric component (2 +/- 0.6) of the LES as compared to those in controls (15 +/- 5 and 12 +/- 4, respectively; p < 0.05); nitrinergic neurons in the gastric fundus (3 +/- 1) were significantly reduced in comparison to those of controls (10 +/- 2) (p < 0.05). CONCLUSIONS: Our results indicate that achalasia is a motor disorder with an intrinsic inhibitory denervation of the esophageal and gastric component of the LES and of the proximal stomach, thus providing further evidence for an extraesophageal extension of the disease.

How should Helicobacter pylori negative patients be managed?

Dyspepsia is a digestive syndrome distinct from (although frequently overlapping with) gastro-oesophageal reflux disease (GORD) and irritable bowel syndrome (IBS), which is characterised by various combinations of painful and non-painful symptoms arising from the epigastrium. Dyspepsia can be secondary to a variety of diseases, but in most instances it is idiopathic. Helicobacter pylori infection is responsible for the majority of peptic ulcers and of other diseases potentially associated with dyspepsia. Nevertheless, a causal role for H pylori infection in symptom occurrence has not been established. Experimental data indicate that H pylori eradication does not improve symptoms in the majority of dyspeptic patients. It has been proposed recently that H pylori negative patients should be managed according to their clinical presentation. Some reports suggest that taking into consideration the most relevant or "predominant" symptom may help to identify distinct subgroups among dyspeptic patients with different underlying pathophysiological abnormalities and different responses to treatment. Well designed and conducted prospective studies are needed to verify whether treatment of H pylori negative dyspeptic patients based on the predominant symptom actually is a cost effective approach.

Predominant symptoms identify different subgroups in functional dyspepsia.

OBJECTIVE: Dyspepsia is a common syndrome that often defies diagnosis. Whether the unexplained (or "functional") dyspepsia represents a homogeneous syndrome or includes different subgroups with specific clinical features has not been clarified. The aim of this study was to investigate the relationship between symptom severity, demographic features, and gastric dysmotility in a large series of patients with functional dyspepsia. METHODS: Severity of individual digestive symptoms, demographic features, and scintigraphic gastric emptying of solids were evaluated in 483 patients with chronic unexplained dyspepsia. RESULTS: Two main subgroups were identified. The first was characterized by predominant epigastric pain, male gender (61%), and normal gastric emptying. The second subgroup was characterized by predominant nonpainful symptoms, female gender (60%), a high frequency of associated irritable bowel syndrome (30%), and delayed gastric emptying (42%). A third group included approximately one-third of patients who did not present with any predominant symptom, and was characterized by a high frequency of delayed gastric emptying (30%), overlapping irritable bowel syndrome (28%), and gastroesophageal reflux disease (41%). CONCLUSIONS: Different subgroups exist among patients with functional dyspepsia seen in a referral center. They can be identified by the predominant symptom and are characterized by different demographic, clinical, and pathophysiological features.