Achalasia is an esophageal disorder in which peristalsis is absent and the lower esophageal sphincter fails to relax with swallowing. Patients exhibit difficulties with oral intake that are often associated with dysphagia, regurgitation, aspiration, and weight loss. The diagnosis is best established with esophageal manometry, a technology that now provides sufficient resolution such that achalasia patients can be stratified into clinical subtypes. Several genetically modified animal models have been able to recapitulate the disease, which may provide valuable insights into achalasia's pathogenesis. One such model incorporated a mutation in the Nitric Oxide Synthase 1 (NOS1) gene, which is responsible for the production of nitric oxide, an established smooth muscle relaxant. In this issue of Gastroenterology, Shteyer et al report on the characterization of 2 human cases of achalasia. The cases involve 2 siblings who are the children of Arab parents that are first cousins. The 2 children suffered from dysphagia, repetitive vomiting, and failure to thrive. High-resolution manometry diagnosed the children as suffering from type III achalasia, which is distinguished by lumen-obliterating esophageal spasms (Figure 1). One child underwent exome analysis that revealed a premature stop codon in the NOS1 gene, which was predicted to result in a truncated protein. NOS1 protein participates in the assembly of cofactors that are necessary for the production of nitric oxide. Previous work in NOS1 knockout mice demonstrated that the lower esophageal sphincter pressure was higher. In the present study, the authors expressed both wild-type and the truncated forms of NOS1 in a cell line and established that the mutation was defective in producing nitric oxide. Realizing the defect in nitric oxide production, the authors treated the 2 children with sildenafil, a drug that blocks phosphodiesterase type 5, which normally breaks down cyclic guanosine monophosphate, a second messenger of nitric oxide activity. Treatment of the children with sildenafil resulted in improved abilities to drink liquids and swallow solids. The improvement in symptoms, however, was not associated with an improvement in the esophagram. Regardless, the study demonstrated that a naturally occurring truncating mutation in NOS1 is associated with achalasia, which establishes the importance of nitric oxide first observed in the murine model. See page 533. The worldwide obesity epidemic and the associated rising prevalence of diabetes and the metabolic syndrome have resulted in an increasing prevalence of nonalcoholic fatty liver disease. Nonalcoholic steatohepatitis (NASH), defined as hepatic steatosis in association with inflammation and ballooning degeneration, may ultimately progress to cirrhosis and its complications, including hepatocellular carcinoma (HCC), requiring liver transplantation. Currently, the 4 top causes of chronic liver disease in patients on liver transplant waitlists are chronic hepatitis C virus (HCV) infection, alcoholic liver disease (ALD), NASH, and a combination of chronic HCV infection and ALD (HCV/ALD). However, NASH has been predicted to become the most common indication for liver transplantation within the next 2 decades and, although chronic HCV infection is the most common cause of HCC in patients undergoing liver transplantation, recently NASH was found to be the most rapidly growing indication for liver transplantation in patients with HCC in the United States. In this issue of Gastroenterology (accompanied by an editorial by Sumeet Asrani and Jacqueline O’Leary), Wong et al, using United Network for Organ Sharing and Organ Procurement and Transplantation Network registry data from 2004 to 2013, evaluate retrospectively the specific impact of NASH-related chronic liver disease on liver transplant waitlist registrations. Patients with NASH on waitlists were older at the time of registration and, as expected, had higher body mass index and higher rates of concurrent diabetes mellitus compared with patients with HCV or ALD. Concurrent HCC was present in 25% of patients with chronic HCV infection, 21% of patients with NASH, 13% of patients with HCV/ALD, and 8% of patients with ALD. During the study period, NASH increased 170% as an etiology of chronic liver disease among new liver transplant waitlist registrants, becoming the second leading etiology in 2013. During the same period, new waitlist registrants with ALD increased 45%, registrants with chronic HCV infection increased 14%, and registrants with HCV/ALD decreased by 9% (Figure 2). Although patients with ALD had the highest Model for End-Stage Liver Disease scores at the time of registration, after multivariate adjustment, they were more likely to survive 90 days on the liver transplant list than patients with NASH. No difference was observed in 90-day waitlist survival rates among patients with chronic HCV infection and HCV/ALD compared with patients with NASH. Patients with ALD were the most likely to undergo liver transplantation at 90 days, whereas patients with NASH were the least likely. Patients with chronic HCV infection and HCV/ALD had lower 1-year waitlist survival compared with patients with NASH, despite a greater probability of liver transplantation. These findings demonstrate the changing epidemiology of patients awaiting liver transplantation in the United States and suggest that etiology-specific variations in progression of disease may contribute to etiology-specific differences in the probability of undergoing liver transplantation. Given the likely continued increase in the number of patients with NASH awaiting liver transplantation in the face of expected lower donor availability in the future, efforts to improve waitlist survival and opportunities for liver transplantation for these patients are required. See page 547; and editorial on page 493. Pancreatic cancer remains among the most lethal human cancers, representing the fourth-leading cause of cancer-related death in America. The overall 4-year survival rate is 6%. Potentially curative operative resection is indicated for about 20% of afflicted patients. Thus, improved patient screening and treatment are clearly needed. Patients with increased risk for pancreatic cancer may benefit from earlier and more aggressive screening. Such patients may also be candidates for potential treatments that decrease cancer risk. As a means toward identifying such high-risk patients, Grant et al report in this issue of Gastroenterology (accompanied by an editorial by Jeremy Humphris and colleagues) their efforts to determine the prevalence of germline mutations in pancreatic cancer for genes that are associated with human neoplasias. The authors randomly selected 290 probands from the Ontario Pancreas Cancer Study in Canada. The subjects were selected from predefined patient groups consisting of those with a family history of pancreatic cancer, a family history of breast or ovarian cancer but not pancreatic cancer, and families with no history of pancreatic, breast, or ovarian cancer. Genomic DNA was extracted from peripheral blood lymphocytes and subjected to next-generation sequencing. Variants were evaluated for the genes APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, and TP53. Eleven mutations were identified and predicted to be pathogenic, which calculates to a prevalence of 3.8% for mutation carriers in the Ontario Pancreas Cancer Study. The number of cases with pathogenic mutations for each gene were 3 in ATM, 1 in BRCA1, 2 in BRCA2, 1 in MLH1, 2 in MSH2, 1 in MSH6, and 1 in TP53. For pancreatic cancer patients carrying one of the pathogenic mutations, there was a significant association with breast cancer or colorectal cancer in the proband or a first-degree relative. There was no significant association between mutation carriers and first-degree relatives with pancreatic cancer. Andrew Biankin discusses in greater depth the implications of this study in an accompanying editorial. See page 556; and editorial on page 496. Alcoholic hepatitis (AH) is a severe inflammatory disorder associated with a poor prognosis, with a 28-day mortality approaching 30%. The leading cause of death in patients with AH is the systemic inflammatory response and multisystem organ failure in the setting of overwhelming bacterial infection, despite enhanced immune activity exhibited by these patients. Programmed cell death 1 (PD1), the T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3) and their respective ligands—PDL1 and galectin-9—are inhibitory receptors that play a critical role in regulating the balance between antipathogen immunity and host immune-mediated damage. However, sustained hyperexpression, mediated by a failure to remethylate the PD1 locus, has been shown to promote a state of immune exhaustion, resulting in persistence of viral infections, increased nosocomial infections, and death. Similarly, up-regulation of TIM3 has been shown to result in T-cell dysfunction. In this issue of Gastroenterology (accompanied by an editorial by Ramon Bataller and Pranoti Mandrekar), Markwick et al investigate these 2 immunoinhibitory pathways and whether their blockade might be of potential therapeutic benefit in patients with AH. Three cohorts of patients were studied: 20 patients with AH and a discriminant function of ≥32, 16 patients with alcoholic cirrhosis who were actively drinking but with stable disease, 12 controls, and 4 patients with chronic hepatitis B-induced cirrhosis to serve as controls with chronic liver disease. Patients with AH demonstrated severely compromised neutrophil and lymphocyte antibacterial immunity, whereas patients with alcoholic cirrhosis exhibited only moderate neutrophil dysfunction and no impairment of lymphocyte antibacterial responses compared to healthy controls. A marked increase in the frequency and expression of PD1 and galectin-9 on CD4 T cells and increased expression of PDL1, TIM-3, and galectin-9 on CD8 T cells was demonstrated in patients with AH compared to controls. Elevated levels of plasma galectin-9 levels were also observed in patients with AH compared with controls and patients with alcoholic cirrhosis. Plasma endotoxin levels were significantly higher in patients with AH and at levels that induced PD1 and TIM-3 expression in T-regulatory cells and CD4 and CD8 T cells from controls, indirectly by stimulating the production of interleukin-10 and tumor necrosis factor from monocytes. Blockade of PD1 and TIM-3 improved the compromised lymphocyte antibacterial immunity in patients with AH; this effect was not observed in patients with alcoholic cirrhosis, controls or patients with chronic hepatitis B-induced cirrhosis (Figure 3). Of note, blockade did not result in the production of proinflammatory cytokines. These findings suggest that PD1 and TIM-3 expression impair specifically antibacterial immunity in AH and that targeted therapy against these immune inhibitory receptors may restore host antipathogen immunity in patients with AH. See page 590; and editorial on page 498. Identifying Molecular Targets to Improve Immune Function in Alcoholic HepatitisGastroenterologyVol. 148Issue 3PreviewAlcoholic liver disease (ALD) is a major cause of liver-related morbidity and mortality worldwide. ALD encompasses a range of disorders including steatosis, steatohepatitis, progressive fibrosis, cirrhosis, and hepatocellular carcinoma.1 In addition, patients with underlying ALD (in most cases cirrhosis) and active drinking can develop an episode of acute-on-chronic liver failure named “alcoholic hepatitis” (AH).2 AH in its severe forms bears a high short-term mortality. In these patients, liver homeostatic function is impaired profoundly and portal pressure is particularly high, leading to life-threating complications such as variceal bleeding, encephalopathy, and hepatorenal syndrome. Full-Text PDF Inherited Susceptibility to Pancreatic Cancer in the Era of Next-Generation SequencingGastroenterologyVol. 148Issue 3PreviewThis issue of Gastroenterology presents a manuscript from Ontario, Canada by Grant et al.1 The study provides early insights into the prevalence of point mutations and small insertions and deletions for a set of 13 well-characterized cancer predisposition genes. The genes they tested using a multigene panel include APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, and TP53. They sampled 290 patients from a population-based cohort of patients with histopathologically confirmed pancreatic ductal adenocarcinoma (PC), who were further grouped based on family history. Full-Text PDF Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients With Pancreatic CancerGastroenterologyVol. 148Issue 3PreviewWe investigated the prevalence of germline mutations in APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, and TP53 in patients with pancreatic cancer. Full-Text PDF The Changing Liver Transplant Waitlist: An Emerging Liver Purgatory?GastroenterologyVol. 148Issue 3PreviewA palpable change has occurred over the last decade in the type of patients listed for liver transplantation (LT): we are listing and transplanting sicker patients at higher Model for End-Stage Liver Disease (MELD) scores with more comorbid conditions.1,2 In this issue of Gastroenterology, Wong et al3 used the United Network for Organ Sharing/ Organ Procurement and Transplantation Network (UNOS/OPTN) registry data to describe these dynamic changes occurring on the liver transplant waiting list from 2004 to 2013. Full-Text PDF Truncating Mutation in the Nitric Oxide Synthase 1 Gene Is Associated With Infantile AchalasiaGastroenterologyVol. 148Issue 3PreviewNitric oxide is thought to have a role in the pathogenesis of achalasia. We performed a genetic analysis of 2 siblings with infant-onset achalasia. Exome analysis revealed that they were homozygous for a premature stop codon in the gene encoding nitric oxide synthase 1. Kinetic analyses and molecular modeling showed that the truncated protein product has defects in folding, nitric oxide production, and binding of cofactors. Heller myotomy had no effect in these patients, but sildenafil therapy increased their ability to drink. Full-Text PDF Nonalcoholic Steatohepatitis Is the Second Leading Etiology of Liver Disease Among Adults Awaiting Liver Transplantation in the United StatesGastroenterologyVol. 148Issue 3PreviewNonalcoholic steatohepatitis (NASH) has been predicted to become the leading indication for liver transplantation (LT) in the United States. However, few studies have evaluated changes in the etiology of liver diseases among patients awaiting LT, and none have focused on the effects of NASH on liver transplant waitlists in the United States. Full-Text PDF Blockade of PD1 and TIM3 Restores Innate and Adaptive Immunity in Patients With Acute Alcoholic HepatitisGastroenterologyVol. 148Issue 3PreviewSusceptibility to bacterial infection is a feature of alcohol-related liver disease. Programmed cell death 1 (PD1), the T-cell immunoglobulin and mucin domain–containing protein 3 (TIM3, also known as hepatitis A virus cellular receptor 2), and their respective ligands—CD274 (also known as PD ligand 1 [PDL1]) and galectin-9—are inhibitory receptors that regulate the balance between protective immunity and host immune-mediated damage. However, their sustained hyperexpression promotes immune exhaustion and paralysis. Full-Text PDF