Pathophysiological studies are mandatory to understand the benefit of proton pump inhibitors in patients with idiopathic pulmonary fibrosis

none4noWe read with great interest the paper by Lee et al on the protective effect of proton pump inhibitors (PPIs) for survival in patients with GERD and idiopathic pulmonary fibrosis (IPF). The Authors reviewed a very large number of consecutive adult patients with IPF (n=786) and concluded that the prevalence of GERD is lower in Korean patients than in other countries and that PPI use for at least 4 months may have a protective effect against IPF-related mortality. Although these data appear interesting, relevant limitations of this study were its retrospective nature and the fact that the diagnosis of GERD was not based on sound methods, in that only 18 out of 107 patients had erosive esophagitis at endoscopy, while the remaining ones had NERD (n=66) or typical reflux symptoms without EGD (n=23). Moreover, no functional tests were performed (or described) in them. This is particularly relevant since it has been shown in previous series that a large number of IPF patients lack of GERD symptoms despite objective evidence of GERD at endoscopy or reflux monitoring. Indeed, in IPF patients a phenomenon so called “silent reflux” has been described and the consequent microaspiration into the lungs has been mainly implicated in the pathogenesis of this condition. In contrast with the paper of Lee et al (1), many previous studies have reported a higher prevalence of GERD in patients with IPF, and this important relationship has been sustained by pathophysiological investigations which allowed to detect objectively the presence of an abnormal reflux. For instance, Lee et al did not mention a study in IPF individuals performed with 24-hour impedance pH monitoring, which is nowadays considered to be the best test for measuring gastroesophageal reflux, also in case of atypical manifestations. In this study, patients with IPF had significantly higher esophageal acid exposure and greater number of acid refluxes than controls, but also weakly acidic refluxes were remarkably increased (9). Furthermore, more bile acids and pepsin were detected in both broncheoalveolar lavage fluid and saliva as strong confirmation of the risk of gastric aspiration in upper airways of these patients. Similarly, in an earlier pathophysiological study in a group of scleroderma patients with various degrees of pulmonary fibrosis based on high resolution computed tomography, not only acid but also weakly acidic refluxes were found much higher in patients with more severe than in those with mild or moderate pulmonary fibrosis (10). In conclusion, we would like to emphasize that reflux monitoring plays a fundamental role in confirming the presence of GERD in IPF patients and, therefore, the benefit of PPI use in them should be evaluated in carefully investigated subjects in order to provide stronger evidence that PPI may be helpful for their well being and survivalnoneSavarino, Edoardo; Zentilin, Patrizia; Marabotto, Elisa; Savarino, VincenzoSavarino, EDOARDO VINCENZO; Zentilin, Patrizia; Marabotto, Elisa; Savarino, Vincenz

Relevance of measuring substances in bronchoalveolar lavage fluid for detecting aspiration-associated extraesophageal reflux disease

We read with great interest the paper by Ozdemir et al (1) on the assay of lipid-laden macrophages (LLMs) in broncho-alveolar lavage (BAL) fluid of patients with chronic cough as a marker of micro-aspiration of refluxate into airways. The Authors found that patients with abnormal extra-esophageal reflux as measured by 24-hour impedance-pH monitoring had higher LLM positivity in BAL specimens than those with normal reflux and accordingly, they suggested that this BAL finding should be used to diagnose aspiration in reflux-related chronic cough. The measurement of LLMs from BAL specimens is one of the most widely used tests to identify aspiration-associated extra-esophageal reflux disease (AERD), particularly in children (2). This test is based on the hypothesis that refluxate is phagocytosed by alveolar macrophages and that staining for those in the BAL fluid would verify the presence of AERD. However, previous studies have demonstrated conflicting results, because an increase in LLMs has been observed not only in reflux patients, but also in those without reflux and in any disorder leading to pulmonary inflammation (3,4). On the other hand, search for pepsin and bile acids in BAL has been shown to represent a more valid and specific biomarker of micro-aspiration in patients with objective evidence of abnormal reflux burden since, up to now, no studies measured their presence in BAL of healthy volunteers or patient-controls without evidence of reflux disease (5). Thus, the detection of the above substances in BAL has been overall considered as a strong confirmation of gastric contents coming up from the stomach into the airways. Ozdemir et al stated that BAL pepsin levels have been studied very poorly to diagnose gastro-esophageal reflux (GERD) in patients with respiratory symptoms and quote the only investigation by Decalmer et al (6), in which the Authors found in controls lower levels of pepsin than those detected in chronic cough patients. However, it must be emphasized that in this study various respiratory conditions beyond GERD were considered to elucidate the presence of unexplained chronic cough and this may have been an important confounding factor. In our laboratory the detection of pepsin and bile acids in BAL of patients with GERD was also performed in a recent study (7) using impedance-pH monitoring, which is nowadays considered to be the best test for measuring gastro-esophageal reflux, also in case of atypical manifestations of GERD (8-10). We found that patients with idiopathic pulmonary fibrosis (IPF) had significantly higher esophageal acid exposure and greater number of acid refluxes than controls, but also weakly acidic refluxes were remarkably increased. Moreover, more bile acids and pepsin were measured in BAL as a sound marker of gastric aspiration in the upper airways of these patients. Further studies carried out in patients with various pulmonary conditions corroborated our findings (11,12). So far, we would like to emphasize that the detection of various substances in BAL can be of great help in the diagnosis of micro-aspiration of refluxate which is able to induce chronic cough and other respiratory symptoms, but the assay of bile acids or pepsin levels seems to provide us with a more valid and reliable marker of contents reaching the larynx and pharynx from the stomach

Surveillance for Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease: Universal or Selective?

Hepatocellular carcinoma (HCC), the most frequent primary liver cancer, is the sixth most common cancer, the fourth leading cause of cancer-related deaths worldwide, and accounts globally for about 800,000 deaths/year. Early detection of HCC is of pivotal importance as it is associated with improved survival and the ability to apply curative treatments. Chronic liver diseases, and in particular cirrhosis, are the main risk factors for HCC, but the etiology of liver disease is rapidly changing due to improvements in the prevention and treatment of HBV (Hepatitis B virus) and HCV (Hepatitis C virus) infections and to the rising incidence of the metabolic syndrome, of which non-alcoholic fatty liver (NAFLD) is a manifestation. NAFLD is now a recognized and rapidly increasing cause of cirrhosis and HCC. Indeed, the most recent guidelines for NAFLD management recommend screening for HCC in patients with established cirrhosis. Screening in NAFLD patients without cirrhosis is not recommended; however, the prevalence of HCC in this group of NAFLD patients has been reported to be as high as 38%, a proportion significantly higher than the one observed in the general population and in non-cirrhotic subjects with other causes of liver disease. Unfortunately, solid data regarding the risk stratification of patients with non-cirrhotic NAFLD who might best benefit from HCC surveillance are scarce, and specific recommendations in this field are urgently needed due to the increasing NAFLD epidemic, at least in Western countries. To further complicate matters, liver ultrasonography, which represents the current standard for HCC surveillance, has a decreased diagnostic accuracy in patients with NAFLD, and therefore disease-specific surveillance tools will be required for the early identification of HCC in this population. In this review, we summarize the most recent evidence on the epidemiology and risk factors for HCC in patients with NAFLD, with and without cirrhosis, and the evidence supporting surveillance for early HCC detection in these patients, reviewing the potential limitations of currently recommended surveillance strategies, and assessing data on the accuracy of potential new screening tools. At this stage it is difficult to propose general recommendations, and best clinical judgement should be exercised, based on the profile of risk factors specific to each patient

Proton pump inhibitors: use and misuse in the clinical setting

Introduction: The introduction of proton pump inhibitors (PPIs) into clinical practice has greatly improved our therapeutic approach to acid-related diseases for their efficacy and safety. Areas Covered: The following evidence-based indications for PPI use are acknowledged by many scientific societies: treatment of the various forms and complications of gastroesophageal reflux disease, eradication of H. pylori infection in combination with two or more antibiotics, short- and long-term therapy of H. pylori-negative peptic ulcers, healing, and prevention of NSAID/COXIB-associated gastric ulcers, co-therapy with endoscopic procedures to control upper digestive bleeding and medical treatment of Zollinger Ellison syndrome. Expert Commentary: Despite the above well-defined indications, however, the use of PPIs continues to grow every year in both western and eastern countries and the endless expansion of the PPI market has created important problems for many regulatory authorities for two relevant features: the progressive increase of the costs of therapy and the greater potential harms for the patients. The major reasons for the misuse of PPIs are the prevention of gastro-duodenal ulcers in patients without risk factors and the stress ulcer prophylaxis in non-intensive care units, steroid therapy alone, anti-platelet or anti-coagulant treatment in patients without risk of gastric injury and the overtreatment of functional dyspepsia

Reduction of hexavalent chromium by fasted and fed human gastric fluid. I. Chemical reduction and mitigation of mutagenicity

Abstract Evaluation of the reducing capacity of human gastric fluid from healthy individuals, under fasted and fed conditions, is critical for assessing the cancer hazard posed by ingested hexavalent chromium [Cr(VI)] and for developing quantitative physiologically-based pharmacokinetic models used in risk assessment. In the present study, the patterns of Cr(VI) reduction were evaluated in 16 paired pre- and post-meal gastric fluid samples collected from 8 healthy volunteers. Human gastric fluid was effective both in reducing Cr(VI), as measured by using the s-diphenylcarbazide colorimetric method, and in attenuating mutagenicity in the Ames test. The mean (± SE) Cr(VI)-reducing ability of post-meal samples (20.4 ± 2.6 μg Cr(VI)/mL gastric fluid) was significantly higher than that of pre-meal samples (10.2 ± 2.3 μg Cr(VI)/mL gastric fluid). When using the mutagenicity assay, the decrease of mutagenicity produced by pre-meal and post-meal samples corresponded to reduction of 13.3 ± 1.9 and 25.6 ± 2.8 μg Cr(VI)/mL gastric fluid, respectively. These data are comparable to parallel results conducted by using speciated isotope dilution mass spectrometry. Cr(VI) reduction was rapid, with > 70% of total reduction occurring within 1 min and 98% of reduction is achieved within 30 min with post-meal gastric fluid at pH 2.0. pH dependence was observed with decreasing Cr(VI) reducing capacity at higher pH. Attenuation of the mutagenic response is consistent with the lack of DNA damage observed in the gastrointestinal tract of rodents following administration of ≤ 180 ppm Cr(VI) for up to 90 days in drinking water. Quantifying Cr(VI) reduction kinetics in the human gastrointestinal tract is necessary for assessing the potential hazards posed by Cr(VI) in drinking water

Vonoprazan Fumarate for the Treatment of Gastric Ulcers: A Short Review on Emerging Data

Potassium-competitive acid blockers (P-CABs), such as vonoprazan, represent a novel and heterogeneous class of drugs that competitively block the potassium binding site of gastric H+/K+ ATPase, thus potentially overcoming the limitations of proton-pump inhibitors. Different studies evaluated the efficacy of vonoprazan versus proton-pump inhi-bitors (PPIs) for the treatment of acid-related disorders, and, therefore, P-CABs present the same indications of PPIs: gastroesophageal reflux disease, gastric and duodenal ulcer heal-ing, management of upper gastrointestinal bleeding, non-steroidal anti-inflammatory drug (NSAID)-associated ulcers and Helicobacter pylori eradication therapy. The aim of this review was to evaluate the role of vonoprazan for the treatment of peptic ulcer disease (PUD) and the management of gastric ulcer occurring after endoscopic submucosal dissection (ESD). Indeed, vonoprazan (at the dose of both 10 and 20mg) showed similar results to PPIs in patients taking long-term NSAIDs, in the absence of severe adverse effects, and provided a more rapid and effective treatment of ulcers induced by ESD. However, studies in medical literature are heterogeneous, mainly performed with a retrospective design, and often carried out in Japan only. For these reasons, further prospective, randomized studies are warranted in order to help physicians, patients, and policymakers regarding the use of vonoprazan in clinical practice

Vonoprazan for treatment of gastroesophageal reflux: pharmacodynamic and pharmacokinetic considerations

This review provides an update on the pharmacokinetic properties of vonoprazan and their correlates with pharmacodynamics; preliminary data on the therapeutic efficacy of vonoprazan as compared to lansoprazole in GERD patients Expert opinion: At variance from all available PPIs, vonoprazan acts directly on H+,K+-ATPase irrespectively of its activity, providing a fast onset of action without requiring acid activation and specific administration timing. Clinical and pharmacological investigations have confirmed a more rapid, potent and prolonged inhibition of acid secretion, including a better nighttime acid control, and a less antisecretory variability, as compared with PPIs. Preliminary data in patients with erosive esophagitis (EE) have shown the non-inferiority of vonoprazan to lansoprazole in terms of symptom relief and healing rate. Since these pharmacokinetic advantages, it is expected that it will have a significant favorable impact on GERD management. However, the clinical use of vonoprazan raises also some issues about its efficacy and safety in the long-term that deserve verification and careful investigation

Optimal management of constipation associated with irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common chronic functional disorder of the gastrointestinal tract, meanly characterized by recurrent abdominal pain or discomfort and altered bowel habit. It is a complex disorder involving biological, environmental, and psychosocial factors. The diagnosis is achieved according to the Rome III criteria provided that organic causes have been excluded. Although IBS does not constitute a life-threatening condition, it has a remarkable prevalence and profoundly reduces the quality of life with burdening socioeconomic costs. One of the principal concerns about IBS is the lack of effective therapeutic options. Up to 40% of patients are not satisfied with any available medications, especially those suffering from chronic constipation. A correct management of IBS with constipation should evolve through a global approach focused on the patient, starting with careful history taking in order to assess the presence of organic diseases that might trigger the disorder. Therefore, the second step is to examine lifestyle, dietary habits, and psychological status. On these bases, a step-up management of disease is recommended: from fiber and bulking agents, to osmotic laxative drugs, to new molecules like lubiprostone and linaclotide. Although new promising tools for relief of bowel-movement-related symptoms are being discovered, a dedicated doctor-patient relationship still seems to be the key for success

Mediterranean Diet and NAFLD: What We Know and Questions That Still Need to Be Answered

open8Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is expected to become the leading cause of end-stage liver disease worldwide over the next few decades. In fact, NAFLD encompasses different clinical scenarios, from the simple accumulation of fat (steatosis) to steatohepatitis (NASH), NASH-cirrhosis, and cirrhosis complications. In this context, it is fundamental to pursue strategies aimed at both preventing the disease and reducing the progression of liver fibrosis once liver damage is already initiated. As of today, no pharmacological treatment has been approved for NAFLD/NASH, and the only recommended treatment of proven efficacy are life-style modifications, including diet and physical exercise pointing at weight loss of 5%-7%. Different dietetic approaches have been proposed in this setting, and in this review, we will discuss the evidence regarding the efficacy of the Mediterranean Diet as a treatment for NAFLD. In particular, we will report the effects on liver-related outcomes.openPlaz Torres, Maria Corina; Aghemo, Alessio; Lleo, Ana; Bodini, Giorgia; Furnari, Manuele; Marabotto, Elisa; Miele, Luca; Giannini, Edoardo GPlaz Torres, Maria Corina; Aghemo, Alessio; Lleo, Ana; Bodini, Giorgia; Furnari, Manuele; Marabotto, Elisa; Miele, Luca; Giannini, Edoardo

Optimal management of constipation associated with irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a common chronic functional disorder of the gastrointestinal tract, meanly characterized by recurrent abdominal pain or discomfort and altered bowel habit. It is a complex disorder involving biological, environmental, and psychosocial factors. The diagnosis is achieved according to the Rome III criteria provided that organic causes have been excluded. Although IBS does not constitute a life-threatening condition, it has a remarkable prevalence and profoundly reduces the quality of life with burdening socioeconomic costs. One of the principal concerns about IBS is the lack of effective therapeutic options. Up to 40% of patients are not satisfied with any available medications, especially those suffering from chronic constipation. A correct management of IBS with constipation should evolve through a global approach focused on the patient, starting with careful history taking in order to assess the presence of organic diseases that might trigger the disorder. Therefore, the second step is to examine lifestyle, dietary habits, and psychological status. On these bases, a step-up management of disease is recommended: from fiber and bulking agents, to osmotic laxative drugs, to new molecules like lubiprostone and linaclotide. Although new promising tools for relief of bowel-movement-related symptoms are being discovered, a dedicated doctor\u2013patient relationship still seems to be the key for succes