The Montreal Definition and Classification of Gastroesophageal Reflux Disease: A Global Evidence-Based Consensus

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About the National Institute for Health and Care Excellence - NICE.

ContextThe efficient sequestration of hemoglobin by the red blood cell membrane
and the presence of multiple hemoglobin clearance mechanisms suggest a critical
need to prevent the buildup of this molecule in the plasma. A growing list
of clinical manifestations attributed to hemoglobin release in a variety of
acquired and iatrogenic hemolytic disorders suggests that hemolysis and hemoglobinemia
should be considered as a novel mechanism of human disease.Evidence AcquisitionPertinent scientific literature databases and references were searched
through October 2004 using terms that encompassed various aspects of hemolysis,
hemoglobin preparations, clinical symptoms associated with plasma hemoglobin,
nitric oxide in hemolysis, anemia, pulmonary hypertension, paroxysmal nocturnal
hemoglobinuria, and sickle-cell disease.Evidence SynthesisHemoglobin is released into the plasma from the erythrocyte during intravascular
hemolysis in hereditary, acquired, and iatrogenic hemolytic conditions. When
the capacity of protective hemoglobin-scavenging mechanisms has been saturated,
levels of cell-free hemoglobin increase in the plasma, resulting in the consumption
of nitric oxide and clinical sequelae. Nitric oxide plays a major role in
vascular homeostasis and has been shown to be a critical regulator of basal
and stress-mediated smooth muscle relaxation and vasomotor tone, endothelial
adhesion molecule expression, and platelet activation and aggregation. Thus,
clinical consequences of excessive cell-free plasma hemoglobin levels during
intravascular hemolysis or the administration of hemoglobin preparations include
dystonias involving the gastrointestinal, cardiovascular, pulmonary, and urogenital
systems, as well as clotting disorders. Many of the clinical sequelae of intravascular
hemolysis in a prototypic hemolytic disease, paroxysmal nocturnal hemoglobinuria,
are readily explained by hemoglobin-mediated nitric oxide scavenging.ConclusionA growing body of evidence supports the existence of a novel mechanism
of human disease, namely, hemolysis-associated smooth muscle dystonia, vasculopathy,
and endothelial dysfunction.

https://jamanetwork.com/journals/jama/articlepdf/200611/JCR50001.pdf

The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease.

A SNP in the gene encoding lactase (LCT) (C/T-13910) is associated with the ability to digest milk as adults (lactase persistence) in Europeans, but the genetic basis of lactase persistence in Africans was previously unknown. We conducted a genotype-phenotype association study in 470

/pdf/convergent-adaptation-of-human-lactase-persistence-in-africa-4exuxz9ryv.pdf

Convergent adaptation of human lactase persistence in Africa and Europe

Evidence suggests that drug-induced gastrointestinal (GI) injury is common, with a wide range of medications implicated, but an accurate estimate of the incidence of adverse GI reactions to drugs is difficult to obtain. Data from the United States (Food and Drug administration) show that 18 percent of all adverse reactions reported to that agency were related to the GI tract.1 Diarrheal episodes are classically distinguished into acute and chronic (or persistent) based on their duration. Acute diarrhea is thus defined as an episode that has an acute onset and lasts no longer than 14 days; chronic or persistent diarrhea is defined as an episode that lasts longer than 14 days. The distinction, supported by the World Health Organization (WHO), has implications not only for classification and epidemiological studies but also from a practical standpoint because protracted diarrhea often has a different set of causes, poses different problems of management, and has a different prognosis. Drugs can induce intestinal injury or dysfunction through single or multiple mechanisms. The more common mechanisms of drug induced bowel injury are listed below. This discussion covers antibiotic agents that have been associated with some effect.

Clinical practice. Antibiotic-associated diarrhea.

Only 10%-20% of all cases of antibiotic-associated diarrhea (AAD) are caused by infection with Clostridium difficile. Other infectious organisms causing AAD include Clostridium perfringens, Staphylococcus aureus, Klebsiella oxytoca, Candida species, and Salmonella species. Most of the clinically mild AAD cases are due to functional disturbances of intestinal carbohydrate or bile acid metabolism, to allergic and toxic effects of antibiotics on intestinal mucosa, or to pharmacological effects on motility. Saccharomyces boulardii and Enterococcus SF68 can reduce the risk of developing AAD. Patients receiving antibiotic treatment should avoid food containing high amounts of poorly absorbable carbohydrates. Mild cases of AAD that may or may not be caused by C. difficile can be resolved by discontinuation of antibiotic therapy and by dietary carbohydrate reduction. Only severe AAD caused by C. difficile requires specific antibiotic treatment.

https://www.jstor.org/stable/pdfplus/4481611.pdf

Mechanisms and Management of Antibiotic-Associated Diarrhea

Background and aims: Sildenafil blocks phosphodiesterase type 5 which degrades nitric oxide (NO) stimulated 3`5`-cyclic monophosphate (cGMP), thereby relaxing smooth muscle cells in various organs. We used sildenafil as a tool to investigate the role of the NO-cGMP pathway in the oesophagus of healthy volunteers and patients with hypercontractile oesophageal motility disorders.

Methods: Six healthy male volunteers participated in a randomised double blind study on two separate days before and one hour after oral intake of either sildenafil 50 mg or placebo. Oesophageal manometry was performed to determine vector volume of the lower oesophageal sphincter (LOS) and pressure amplitudes of the oesophageal body. Four of the volunteers underwent 12 hour ambulatory oesophageal manometry on two separate days, once with sildenafil 50 mg and once with placebo. An activity index for spontaneous swallowing was calculated for every hour of the study. Eleven patients with hypercontractile oesophageal motility disorders took part in an open study of the effect of 50 mg sildenafil on manometric features of their disorder and on the clinical response to sildenafil taken as required.

Results: In healthy subjects, sildenafil significantly reduced LOS pressure vector volume and pressure amplitudes in the distal half of the oesophageal body. In three of four subjects the inhibitory effect of sildenafil lasted at least eight hours. In nine of 11 patients, manometric improvement after sildenafil was observed but only four had an improvement in oesophageal symptoms with sildenafil taken as required. Two of these four patients however experienced side effects and did not want to continue treatment.

Conclusions: Sildenafil lowers LOS pressure and propulsive forces in the body of the oesophagus of healthy subjects as well as in patients with nutcracker oesophagus, hypertensive LOS, and achalasia. The effect of sildenafil on the oesophageal body may last for up to eight hours in healthy volunteers. A subset of patients with hypertensive LOS or nutcracker oesophagus may benefit from sildenafil but side effects are a limiting factor.

https://gut.bmj.com/content/gutjnl/50/6/758.full.pdf

Effect of sildenafil on oesophageal motor function in healthy subjects and patients with oesophageal motor disorders.

Background: The optimal management of patients with reflux-associated laryngitis is unclear. We performed a placebo-controlled crossover trial in patients with proven reflux disease and associated laryngitis to determine the effect of pantoprazole and to gain information on the natural course of the disease. Methods: Sixty-two consecutive non-smoking patients with hoarseness and proven laryngitis were examined. Scores with respect to the larynx and for subjective complaints were determined and 24-h pH-metry to assess acid reflux in the lower oesophagus and pharynx was performed. Patients with pathologic reflux were given the chance to enter a double-blinded randomized crossover trial with pantoprazole 40 mg b.i.d. and placebo for a duration of 3 months each, separated by a 2-week washout period. Results: Twenty-four of 62 patients showed pathological reflux; 21 patients were included in the study and 14 concluded all parts of the study. Both pantoprazole and placebo resulted in a marked improvement in lar...

Effect of pantoprazole on the course of reflux-associated laryngitis: a placebo-controlled double-blind crossover study.

Background and aims Recent publications have found that the CC genotype of the DNA variant -13910 T/C upstream of the LCT gene is associated with lactase non-persistence. We therefore compared the value of DNA testing for this variant (DNA test) with the lactose hydrogen breath test (H 2 test), which is the clinical standard for the diagnosis of lactase non-persistence. Patients and methods One hundred and twenty-three consecutive patients with suspected lactose malabsorption were tested for the presence of the -13910 T/C variant by polymerase chain reaction-restriction fragment length polymorphism analysis. These patients also underwent the H 2 test after ingestion of 50 g lactose. Results Thirty-seven subjects had a CC genotype of the -13910 T>C polymorphism suggesting lactase non-persistence; 36 (97%) had also a positive H 2 test Eighty-six subjects had either a TC or a TT genotype suggestive of lactase persistence. Seventy-four (86%) of these tested negative on the H 2 test, while 12 patients had a positive H 2 test. In eight of these 12 patients duodenal biopsies showed no evidence of small bowel disease. One patient carrying a CC genotype had a negative H 2 test. In this patient the rise in serum glucose after oral lactose was normal, furthermore H 2 non-excretion was also excluded. Conclusions An excellent correlation is observed between a CC genotype and a positive H 2 test, whereas the correlation between a TC or TT genotype and a negative H 2 test result is less strong. Analysis of the -13910 T/C variant can be considered a good test for predicting the presence of lactase non-persistence in a patient population with suspected lactose malabsorption.

Evaluation of a new DNA test compared with the lactose hydrogen breath test for the diagnosis of lactase non-persistence.

Background and aims: Chemonociception in the human small intestine has not been studied extensively. Although capsaicin can cause intestinal sensations, it is not known if this is due to stimulation of chemoreceptors or to motor changes. Our aims were to evaluate motor activity during capsaicin induced nociception and to compare qualities of jejunal nociception induced by capsaicin and mechanical distension. Methods: Twenty nine healthy subjects swallowed a tube with a perfusion site at the ligament of Treitz and, 7 cm distally, a barostat balloon. Phasic motor activity was measured around the perfusion site and the balloon. Capsaicin solutions (40, 200, and 400 μg/ml) 2.5 ml/min were perfused for 60 minutes or until severe discomfort occurred. A graded questionnaire for seven different sensations was completed every 10 minutes and after capsaicin perfusion was replaced by saline perfusion because of severe discomfort. Sensations arising from pressure controlled distensions were assessed before and after capsaicin perfusion when sensations had stopped (n = 19), or during capsaicin administration when no discomfort was reported (n = 5). Results: Capsaicin perfusion induced feelings of pressure, cramps, pain, and warmth. The quality and abdominal location of these sensations were similar to those induced by distension, except for warmth (p Conclusion: Despite the similarities in abdominal localisation and perceptional quality of capsaicin and distension induced sensations, our results rule out the fact that abdominal discomfort evoked by capsaicin involves sensitisation of mechanoreceptors or an increase in phasic and tonic motor activity. Capsaicin evokes abdominal sensations by stimulation of chemoreceptors which proves the existence of chemonociception in the human small intestine.

https://gut.bmj.com/content/gutjnl/53/8/1109.full.pdf

Heinz F. Hammer

Papers

Mechanisms and Management of Antibiotic-Associated Diarrhea

Effect of sildenafil on oesophageal motor function in healthy subjects and patients with oesophageal motor disorders.

Effect of pantoprazole on the course of reflux-associated laryngitis: a placebo-controlled double-blind crossover study.

Evaluation of a new DNA test compared with the lactose hydrogen breath test for the diagnosis of lactase non-persistence.

Chemical nociception in the jejunum induced by capsaicin