A US multicenter study developed a clinical model to estimate the pretest probability of abnormal acid reflux during pH monitoring in patients with refractory heartburn or suspected extraesophageal reflux symptoms who failed proton pump inhibitor therapy. Patients with refractory heartburn or suspected extraesophageal symptoms often undergo pH monitoring to test for acid reflux. Current guidelines recommend pH monitoring off-treatment among patients with a low pretest probability for reflux and monitoring on-treatment for patients with a high pretest probability for reflux. However, the definition of low or high pretest probability is not clear. In this issue of Gastroenterology, Patel et al report a US multicenter, prospective cohort study enrolling 214 adult patients with refractory heartburn symptoms and 257 patients with suspected extraesophageal reflux symptoms who had failed at least an 8-week course of twice daily proton pump inhibitor therapy. Patients underwent 48-hour wireless pH monitoring while they were off acid-suppressive treatment for ≥7 days. Moderate-to-severe reflux (>12% of time spent at a pH of <4) was found in 23% of patients with refractory heartburn symptoms. Based on their modeling, all patients with refractory heartburn symptoms met criteria for a low pretest probability and could undergo pH monitoring off-treatment. Among patients with suspected extraesophageal reflux symptoms, moderate to severe reflux was detected in 22% patients. They developed a scoring system which assigned 1 point for the presence of any of the following factors: concomitant heartburn, body mass index >25 kg/m2, and asthma. Patients with a score of ≥3 met the criteria for high pretest probability for moderate to severe reflux and could undergo pH monitoring on-treatment. Patients with a score of ≤2 met criteria for low pretest probability moderate to severe reflux and could undergo pH monitoring off-treatment. Validation was performed using an external cohort. Based on these results, clinicians can consider using a novel prediction tool to better use diagnostic testing among patients with refractory acid reflux symptoms. See page 1729. In a US Veteran’s Health Administration cohort, nonalcoholic fatty liver disease was associated with a 7-fold increased risk of hepatocellular carcinoma. Although nonalcoholic fatty liver disease has become the leading cause of chronic liver disease in the United States, the risk of hepatocellular carcinoma among this population is largely unknown. In this issue of Gastroenterology, Kanwal et al performed a retrospective, matched cohort study among 130 facilities in the Veterans Health Administration to estimate the incidence rate of hepatocellular carcinoma among patients with nonalcoholic fatty liver disease. A total of 490 patients with nonalcoholic fatty liver disease developed hepatocellular carcinoma during 2,382,289 person-years of follow-up. The incidence of hepatocellular carcinoma was significantly higher among patients with nonalcoholic fatty liver disease (0.21/1000 person-years) compared with gender- and age-matched controls (0.02/1000 person-years) in a competing risk model (hazard ratio, 7.62; 95% confidence interval, 5.76–10.09; Figure 1). Among patients with nonalcoholic fatty liver disease, those with cirrhosis had the highest incidence of hepatocellular carcinoma (10.6/1000 person-years), the risk being highest in older Hispanics. One-fifth of patients with hepatocellular carcinoma with nonalcoholic fatty liver disease did not have evidence of cirrhosis. These results help to quantify the increase in risk of hepatocellular carcinoma among patients with nonalcoholic fatty liver disease. The absolute risk of hepatocellular carcinoma for most patients with nonalcoholic fatty liver disease was higher than the accepted thresholds for hepatocellular carcinoma screening. However, the absolute risk of hepatocellular carcinoma among patients with nonalcoholic fatty liver disease who do not develop cirrhosis seems to be too low to warrant hepatocellular carcinoma screening. See page 1828. Antibodies generated with a novel human 3D jejunal organoid system neutralize the human norovirus strain GII.4 Sydney. One of the most common causes of gastroenteritis, norovirus, infects an estimated one-half billion people each year, causing 200,000 deaths worldwide. Unfortunately, the tremendous antigenetic variability in norovirus strains has hampered the development of effective vaccines. Of the 7 genogroups (GI–GVII), GII.4 Sydney currently dominates the pool of circulating strains. Researchers have little clarity about how the immune system generates an antibody response to detect and clear infection. This issue of Gastroenterology features a study by Alvarado et al of IgA the human monoclonal antibodies that bind to GII.4 Sydney virus-like particles. The authors found that these antibodies have neutralizing capabilities. Using a newly developed human intestinal organoid 3-dimensional culture system, they cultured norovirus and tested the generated panel of antibodies for growth inhibition and viral neutralization. Approximately two-thirds of the monoclonal antibodies effectively inhibited GII.4 Sydney viral-like particles from binding to porcine gastric membranes and neutralized live human norovirus. From competition-binding assays, the authors determined that the antibodies recognized antigenic sites on the protruding P viral domain. These newly generated antibodies may have therapeutic and diagnostic utility in the management and treatment of human norovirus. This study highlights the power of leveraging human 3-dimensional intestinal organoid cultures in modeling disease and testing therapeutic strategies. See page 1898. Macrophage-derived STING activates type I interferon responses in diet-induced nonalcoholic fatty liver disease, causing hepatocyte inflammatory response and steatosis. Nonalcoholic fatty liver disease (NAFLD) is increasing in parallel with the obesity epidemic. Although generally benign, NAFLD can progress to nonalcoholic steatohepatitis and cause prominent inflammatory liver injury, cirrhosis, and failure. Innate immunity, in particular macrophage dysfunction, seem to be underlying the pathophysiologic contributors to NAFLD’s development; however, the regulation of macrophage functions remains unclear, nor do researchers understand how innate immunity impacts proinflammatory liver pathways. Transmembrane protein 172 (STING) activates the type I interferon immune response in the setting of endoplasmic reticulum stress, viral infection, and carbon tetrachloride-induced liver injury, yet STING’s precise role in these processes is poorly understood. For this issue of Gastroenterology, Luo et al investigated how STING contributes to NAFLD. They first demonstrated that mice induced to develop NAFLD after receiving high-fat diets have STING pathway activation. Turning then to human subjects, the authors determined that STING is increased in mainly Kupffer cells in liver biopsies from NAFLD patients. In comparison with control mice, STING knockout mice were protected from high-fat diet-induced NAFLD, with associated decreased weight gain, body mass, and proinflammatory nuclear factor-κB, tumor necrosis factor-α, IL-1β, and IL-6 levels. When STING knockout mice bone marrow chimeras were reconstituted with wild-type marrow, they lost protection from dietary-induced NAFLD. Results point to a myeloid-derived role for STING in NAFLD development and indicate that STING enhances macrophage proinflammatory signaling, which leads to hepatic steatosis and steatohepatitis via activation of hepatocyte JNK1/nuclear factor-κB pathways (Figure 2). Additional studies on the function of STING’s response to viral infection and the role of STING in human disease are necessary. Nonetheless, this work by Luo et al suggests that STING may represent a new therapeutic target in NAFLD. See page 1971; editorial on page 1687. Model to Select On-Therapy vs Off-Therapy Tests for Patients With Refractory Esophageal or Extraesophageal SymptomsGastroenterologyVol. 155Issue 6PreviewIt is not clear whether we should test for reflux in patients with refractory heartburn or extraesophageal reflux (EER) symptoms, such as cough, hoarseness, or asthma. Guidelines recommend testing patients by pH monitoring when they are on or off acid-suppressive therapies based on pretest probability of reflux, determined by expert consensus. However, it is not clear what constitutes a low or high pretest probability of reflux in these patients. We aimed to develop a model that clinicians can use at bedside to estimate pretest probability of abnormal reflux. Full-Text PDF Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in MiceGastroenterologyVol. 155Issue 6PreviewTransmembrane protein 173 (TMEM173 or STING) signaling by macrophage activates the type I interferon-mediated innate immune response. The innate immune response contributes to hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). We investigated whether STING regulates diet-induced in hepatic steatosis, inflammation, and liver fibrosis in mice. Full-Text PDF Macrophages Steal STING From the Infectious Disease Playbook to Promote Nonalcoholic Fatty Liver DiseaseGastroenterologyVol. 155Issue 6PreviewThe stimulator of interferon genes (STING) is a member of a large family of pattern recognition receptors that sense danger signals within cells and activate innate immune responses.1 STING specifically recognizes and responds to nucleic acids present in the cytosol. When activated by nucleic acids, STING triggers a series of events resulting in the production of type I interferons and proinflammatory cytokines2; as such, STING plays a critical role in antimicrobial host defense.3 The classical ligands for STING are double-stranded DNA molecules from viruses or bacteria. Full-Text PDF Risk of Hepatocellular Cancer in Patients With Non-Alcoholic Fatty Liver DiseaseGastroenterologyVol. 155Issue 6PreviewThere are limited data on the risk of hepatocellular cancer (HCC) in patients with non-alcoholic fatty liver disease (NAFLD). We aimed to estimate the risk of incident HCC among patients with NAFLD. Full-Text PDF Human Monoclonal Antibodies That Neutralize Pandemic GII.4 NorovirusesGastroenterologyVol. 155Issue 6PreviewHuman noroviruses are responsible for approximately 200,000 deaths worldwide each year. In 2012, the GII.4 Sydney strain emerged and became the major circulating norovirus strain associated with human disease. Our understanding of the human norovirus-specific antibody response is limited because few human monoclonal antibodies (mAbs) to noroviruses have been described, and there are no functional assays to measure virus neutralization. We studied the antibody-mediated response to the genogroup (G) II.4 strain by isolating mAbs to GII.4 from infected patients and developing virus neutralization assays. Full-Text PDF