Biomedical subjects
Publications and source records attributed to G N Verne.
The concepts of visceral hyperalgesia and visceral hypersensitivity have been examined in a variety of functional gastrointestinal disorders (FGIDs). Although the pathophysiological mechanisms of pain and hypersensitivity in these disorders are still not well understood, exciting new developments in research have been made in the study of the brain-gut interactions involved in the FGIDs.
Irritable bowel syndrome (IBS) is a functional gut disorder the diagnosis of which is based on clinical symptoms as set forth by the Rome criteria. As the population ages, especially with the population of patients >75 years of age expanding greatly over the next 10 years, IBS is becoming one of the most common diseases of the elderly. Thus far, developing treatment strategies for patients with IBS has been difficult because of the lack of pharmacological targets and the wide range of symptomatology. Additionally, demonstration of a therapeutic benefit is difficult in the presence of a high placebo response observed regardless of the therapy employed. Fibre, antidiarrhoeals and antispasmodics all play some role in the symptomatic treatment of IBS. With the evolution of IBS as a disorder of visceral hypersensitivity, new drugs have been developed that target the enteric nervous system. Tricyclic antidepressants (TCAs) have been found to target the enteric neurons and play a role in pain modulation. Currently, the TCAs are recommended only for severe cases of IBS pain. The newest class of drugs to be approved for use in IBS are the serotonin (5-hydroxytryptamine; 5-HT) antagonists. Specifically, the 5-HT3 receptor antagonists have been shown to decrease symptoms in female patients with IBS. A related class of drugs, the 5-HT4 receptor agonists, is being developed for the treatment of constipation-predominant IBS. Further investigation into the role of spinal afferent neurons in visceral hypersensitivity is at the forefront of IBS research. Several experimental drug therapies for IBS are also discussed in this review including N-methyl-D-aspartate receptor antagonists, neurokinin-1 receptor antagonists, octreotide, clonidine and the selective M3 receptor antagonist, zamifenacin.
Constipation is a very frequent problem, particularly in elderly patients. Constipation is a common reason for patients to seek medical advice, and it accounts for a large number of different prescription and over-the-counter medications. In many cases, no definite cause can be found. Most patients respond to conservative therapy with increased fiber and fluid intake alone. Patients with constipation that is more difficult to control or with alarm symptoms (eg, blood in stool, sudden onset, weight loss, or decreasing stool caliber) warrant further investigation. A variety of medical, behavioral, and surgical therapies can be employed to help these more refractory patients.
BACKGROUND & AIMS: Idiopathic achalasia is a motility disorder of the esophagus characterized by incomplete relaxation of the lower esophageal sphincter and a loss of normal peristaltic activity in the body of the esophagus. The loss of inhibitory neurons in the distal esophagus, as well as abnormalities in the vagus nerve, dorsal motor nucleus of the vagus nerve, and autonomic nervous system, have been described in achalasia. Although the underlying cause of idiopathic achalasia is unknown, the diffuse neuronal effects found suggest a possible viral or neurodegenerative mechanism. By use of serological methods, a significant association between the HLA-DQ1 phenotype and idiopathic achalasia has been found, suggesting a possible immunogenetic mechanism. To further define immunogenetics in the pathogenesis of idiopathic achalasia, we performed tissue typing in patients with achalasia to determine their specific HLA phenotypes. METHODS: We prospectively studied 32 patients (23 white and 9 black) with idiopathic achalasia. Peripheral blood was collected, and HLA-DR and -DQ typing by polymerase chain reaction with sequence-specific primers was performed. Results were compared with those from 268 racially matched local controls. RESULTS: Idiopathic achalasia and the broad HLA-DQ1 allele were not significantly associated in either population, although a trend was found in white subjects (odds ratio [OR], 2.16; chi2 = 5.36, P corrected [Pc] = 0.0824). Further subtyping in white subjects revealed a significant association between idiopathic achalasia and the DQB1*0602 allele (OR, 3.10; chi2 = 7.32, Pc = 0.0408). A strong trend was also found with the DRB1*15 allele (OR, 2.83; chi2 = 8.11, Pc = 0.0572). In the black population, there was no association between idiopathic achalasia and DQB1*0602 or DRB1*15, but a trend was found with DRB1*12 (OR, 6. 19; chi2 = 5.19, P = 0.0227 uncorrected, Pc = 0.295). CONCLUSIONS: Idiopathic achalasia is associated with HLA alleles in a race-specific manner. These results support an immunogenetic mechanism in the pathogenesis of idiopathic achalasia.
Although the mechanism for neuropathic gastrointestinal motility disturbances in scleroderma is unknown, we have previously described anti-myenteric antibodies in some patients with scleroderma. The aim of this study was to screen patients with scleroderma who had gastrointestinal symptoms for the presence of anti-myenteric neuronal antibodies and then purify the immunoglobulin G (IgG) fraction from serum samples for passive immunization into a rat model and observe for intestinal motility effects. Patients with scleroderma were screened, a serum sample from a patient with high titer anti-myenteric neuronal antibodies was obtained, and IgG was purified. Using a rat model with chronic indwelling intestinal electrodes to measure intestinal myoelectric activity, we passively transferred the IgG from either control subjects or this patient with scleroderma. We immunosuppressed the rats and intraperitoneally injected IgG from control subjects and this patient with scleroderma daily for 7 days. Recordings of myoelectric activity in control injected rats revealed no difference from baseline, but a prolongation in the activity front duration and interval and a disruption were seen after scleroderma IgG injections. IgG from a patient with scleroderma with antimyenteric neuronal antibodies, when passively immunized into a rat model, evokes intestinal myoelectric activity alterations. We hypothesize that these antibodies could account for the gastrointestinal neuropathic motility disturbances seen in scleroderma.
Gastrointestinal motility disorders are common in patients with diabetes. The entire gastrointestinal tract may be involved from the esophagus to the anal sphincter. Before instituting therapy, people with diabetes first require a careful diagnostic evaluation. Treatment includes tight glucose control and the use of antiemetics and prokinetic agents.
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Achalasia is a motility disorder of the esophagus characterized by the loss of inhibitory neurons in the distal esophagus. Although idiopathic in nature, autoimmune mechanisms have been proposed, and we set out to determine the presence of myenteric neuronal antibodies. We prospectively studied 18 patients with well-characterized achalasia (by clinical, x-ray, and manometric evidence), nine with gastroesophageal reflux disease, and analyzed the sera from 22 disease-free controls. Using double-label, indirect immunofluorescence techniques, rat esophageal and intestinal sections were double-labeled with sera (dilutions of 1:50 to 1:400) from the three groups and with neurofilament antibody to localize neurons. Seven of 18 achalasia patients had sera that stained the majority of neurons within plexi in the esophageal and intestinal sections, including both NADPH diaphorase (nitric oxide synthase) -positive and -negative neurons. None of the gastroesophageal reflux patients or the controls showed staining. Neuronal antibodies in achalasia provide an attractive hypothesis to explain this diffuse, possibly immune-based disorder.
Chronic constipation is a common clinical condition that frequently does not respond to routine therapeutic measures. We hypothesized that colchicine would be effective in this condition because we reported that it stimulates intestinal motility in rats and commonly causes diarrhea in patients taking the drug for either gouty arthritis or Familial Mediterranean fever. We prospectively studied seven patients with chronic constipation who were refractory to medical therapy and treated them with oral colchicine 0.6 mg per os three times a day for eight weeks in an open-label pilot study. During the study, the mean number of spontaneous bowel movements significantly increased (P < 0.05) from 1.7 +/- 0.5 noted during routine therapy of constipation with laxatives and enemas to 6.4 +/- 0.7 per week; mean colonic transit time significantly (P < 0.05) decreased from 58.1 +/- 2.5 to 47.1 +/- 5.0 hr; and symptoms of abdominal pain, nausea, and bloating significantly (P < 0.05) improved during therapy with colchicine. Oral colchicine (0.6 mg three times a day) therapy appears to be an a promising treatment for chronic constipation and a placebo-controlled trial is indicated to confirm these findings.
We report the case of a patient with severe diarrhea and malabsorption who was subsequently found to have hypogammaglobulinemia and thymoma (Good's syndrome). The mechanism by which hypogammaglobulinemia and/or thymoma causes diarrhea is unclear. It may be related to malabsorption caused by a mucosal lesion resembling villous atrophy, which may resolve with restoration of immunologic status. Diarrhea in some patients may respond to commercial gamma globulin injections, fresh frozen plasma, or cholestyramine therapy. The etiologic relationship between thymoma and acquired hypogammaglobulinemia remains unclear. Thymectomy is generally ineffective in improving immunologic deficiencies and coexisting conditions in patients with acquired hypogammaglobulinemia. In our patient's case, severe diarrhea resolved after resection of the thymoma.
IBS is one of the most common of the gastrointestinal disease, but it can be a diagnostic challenge because of the many symptoms that overlap with other such diseases. Most common among the symptoms are abdominal pain, a feeling of intestinal distention or bloating, and either diarrhea or constipation. Patients may be found to have an exacerbation of symptoms with stress, and they may have an increased sensitivity to bowel distention. History and physical examination findings often can be relied on to make the diagnosis, avoiding overuse of laboratory testing. Treatment consists of patient education and support, lifestyle and dietary changes, and use of several pharmacologic agents for symptom relief. Antidepressants are being investigated as a possible additional form of treatment.
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Treatment of chronic intestinal pseudoobstruction with prokinetic agents has been disappointing. Our study was designed to determine if octreotide and erythromycin would provide sustained relief from nausea, abdominal pain, and bloating in pseudoobstruction. Using gastrointestinal manometry, quantitative parameters of the activity front of the migrating motor complex at baseline and after prokinetic therapy with erythromycin and octreotide were determined in 14 patients with intestinal pseudoobstruction who had nausea, abdominal pain, and bloating. Patients were treated with erythromycin and octreotide for 20-33 weeks. Octreotide increased the frequency, duration, and motility index of activity fronts (AFs) from 1.2 +/- 0.3 AFs/4 hr, 2.7 +/- 0.7 min, and 85 +/- 23 min mm Hg to 4.1 +/- 0.8 AFs/4 hr, 5.5 +/- 0.7 min, and 152 +/- 24 min mm Hg, respectively (P < 0.05). Antral activity was decreased from 63 +/- 14 to 23 +/- 8% by octreotide (P < 0.05). Erythromycin induced antral activity; however, small intestinal motor activity was suppressed. While on erythromycin and octreotide, five patients had long-term improvement of nausea and abdominal pain. All responders had at least 5 AFs/4 hr induced by octreotide. We conclude that octreotide and erythromycin relieve abdominal pain and nausea in pseudoobstruction. Patients who have at least 5 AFs/4 hr after octreotide administration are most likely to clinically respond.
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Chronic intestinal pseudo-obstruction denotes the clinical picture that results due to the failure of intestinal peristalsis to overcome the normal resistance to flow and is characterized by recurrent episodes of signs and symptoms of intestinal obstruction in the absence of any mechanical compromise of the intestinal lumen. The region(s) of the gut affected may be isolated or diffuse. It is not uncommon to find evidence of autonomic neuropathy and smooth muscle dysfunction with extraintestinal manifestations such as urinary symptoms from abnormal ureter or bladder function. Intestinal pseudo-obstruction can be caused by a variety of diseases, and for simplicity, certain authors have divided it into myopathic and neuropathic categories. Intestinal pseudo-obstruction may present at any age with a variable amount of abdominal pain, distension, nausea, diarrhea, or constipation and with laboratory abnormalities usually reflecting the degree of malabsorption and malnutrition present. The radiologic findings are varied but commonly include paralytic ileus or signs of apparent clinical obstruction with dilated loops of bowel. The number of pseudo-obstruction cases is dependent on how one defines the condition. It appears prudent to require radiographic abnormalities consistent with obstruction on a plain film of the abdomen for the diagnosis. More recently, studies have focused on the gastrointestinal manometric abnormalities of the stomach and small intestine in chronic intestinal pseudo-obstruction during fasting and fed states; however, sensitivity and specificity of these abnormalities are not well defined. Treatment is aimed at limiting symptoms and maintaining adequate nutrition. Prokinetic agents should be tried in an attempt to restore normal intestinal propulsion. However, their overall efficacy appears to be variable. It is still too premature to consider intestinal pacing or small bowel transplantation in this condition. Surgical approaches to chronic intestinal pseudo-obstruction should be limited to patients refractory to medical therapy, and even then, an approach focused on the patient's primary presenting symptoms should be considered.