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Proper mitochondrial function and adequate cellular ATP are necessary for normal pancreatic protein synthesis and sorting, maintenance of intracellular organelles and enzyme secretion. Inorganic phosphate is required for generating ATP and its limited availability may lead to reduced ATP production causing impaired Ca(2+) handling, defective autophagy, zymogen activation, and necrosis, which are all features of acute pancreatitis. We hypothesized that reduced dietary phosphate leads to hypophosphatemia and exacerbates pancreatitis severity of multiple causes. We observed that mice fed a low-phosphate diet before the induction of pancreatitis by either repeated caerulein administration or pancreatic duct injection as a model of pressure-induced pancreatitis developed hypophosphatemia and exhibited more severe pancreatitis than normophosphatemic mice. Pancreatitis severity was significantly reduced in mice treated with phosphate. In vitro modeling of secretagogue- and pressure-induced pancreatic injury was evaluated in isolated pancreatic acini using cholecystokinin and the mechanoreceptor Piezo1 agonist, Yoda1, under low and normal phosphate conditions. Isolated pancreatic acini were more sensitive to cholecystokinin- and Yoda1-induced acinar cell damage and mitochondrial dysfunction under low-phosphate conditions and improved following phosphate supplementation. Importantly, even mice on a normal phosphate diet exhibited less severe pancreatitis when treated with supplemental phosphate. Thus, hypophosphatemia sensitizes animals to pancreatitis and phosphate supplementation reduces pancreatitis severity. These appear to be direct effects of phosphate on acinar cells through restoration of mitochondrial function. We propose that phosphate administration may be useful in the treatment of acute pancreatitis. NEW & NOTEWORTHY Impaired ATP synthesis disrupts acinar cell homeostasis and is an early step in pancreatitis. We report that reduced phosphate availability impairs mitochondrial function and worsens pancreatic injury. Phosphate supplementation improves mitochondrial function and protects against experimental pancreatitis, raising the possibility that phosphate supplementation may be useful in treating pancreatitis.

The aim of this study was to determine if hypophosphatemia is more common in patients with severe alcohol-induced acute pancreatitis (AAP).This is a retrospective, single institution, cohort study that analyzed 147 patients admitted to the hospital for AAP. Multivariate logistic regression was used to determine if hypophosphatemia would be related to clinical outcomes of disease severity.Hypophosphatemia was more common in patients with severe AAP at admission; in addition, all patients with severe AAP (100%) eventually developed hypophosphatemia during admission, relative to those with mild (43%) and moderately severe (54%) AAP. The magnitude of the lowest phosphate measurement obtained during admission was lower in patients with severe AAP (mean, 1.5 mg/dL, standard deviation [SD], 0.5 mg/dL) relative to those with mild (mean, 2.6 mg/dL; SD, 0.9 mg/dL) and moderately severe (mean, 2.3 mg/dL; SD, 0.9 mg/dL) AAP (P0.001). Finally, patients who developed hypophosphatemia during admission were more likely to require intensive care unit admission (P0.001), vasopressors (P = 0.01), or intubation (P = 0.003).Hypophosphatemia is more common and of greater magnitude in patients admitted to the hospital with severe AAP. In addition, patients with severe AAP who develop hypophosphatemia during admission are more likely to have poorer clinical outcomes.

The aim of this study was to determine if the quick Sepsis-Related Organ Failure Assessment (qSOFA) score assessed at and 48 hours after admission is prognostic for alcohol-induced acute pancreatitis (AAP) severity.This is a retrospective cohort review study of 161 patients admitted to a single academic hospital in Houston, TX, with the diagnosis of AAP. Receiver operator characteristics analysis and logistic regression were used to assess the diagnostic accuracy and prognostic ability of the qSOFA score.A qSOFA score of 2 or higher at and 48 hours after admission had a specificity of 94% or greater and sensitivity of 33% or higher for pancreatitis severity and need for intensive care admission, intubation, or vasopressors. The qSOFA score at and 48 hours after admission was prognostic of intensive care unit admission by an adjusted odds ratio of 48.5 (95% confidence interval [CI], 6.4-1013.3; Plt; 0.001) and 18.8 (95% CI, 2.2-467.3; Plt; 0.05), respectively. The qSOFA score at admission was prognostic of severe pancreatitis by an adjusted odds ratio of 35.3 (95% CI, 7.2-224.3; Plt; 0.001).A qSOFA score of 2 or higher is highly specific and prognostic of multiple clinical outcomes both at and 48 hours after admission in patients with AAP.

Background Viral resistance-associated substitutions (RASs) can develop in the setting of DAAs therapy (i.e., emerging RASs). Long-term monitoring of fibrosis regression after achieving SVR to simiprevir (SMV)/sofosbuvir (SOF) is essential. The aim of this study was to determine the prevalence of baseline and emerging NS34A RASs in chronic HCV patients in Upper Egypt and to assess the impact of SMV/SOF therapy on liver stiffness. Results The enrolled 59 patients had HCV genotype 4a without any baseline RASs in the NS34A region. 96.6% (57/59) of patients achieved sustained virological response (SVR12). Of the two patients who failed to achieve SVR12, one of them developed emerging RASs Q80K in the NS34A region. Seventy-two weeks after SMV/SOF therapy, the percentage of patients with liver fibrosis stage (F2, F3, and F4) decreased from 75.4% before treatment to 42.1% after treatment. The combination of SOF and SMV appeared to be well tolerated. Conclusions All patients had HCV genotype 4a without any baseline RASs in the NS34A region. In addition, there was improvement of non-invasive measures of liver fibrosis in patients who achieved SVR, 72 weeks after SMV/SOF therapy.

Background& aim: HCV infection is one of the major health problems in our country. Prevalence of DM is higher among patients with chronic HCV infection. Insulin resistance (IR) is common in such and its impact on sustained virological response (SVR) is not well studied. This work was designed to assess impact of IR on SVR. Patients & methods: Between July 2016 and June 2017; 200 patients with chronic HCV infection were enrolled in a prospective study. Exclusion criteria included decompensated cirrhosis, hepatocellular carcinoma or extrahepatic malignancy, co-infection with HBV or HIV infection. HOMA and IR were assessed at baseline of therapy and 3-months post-therapy. Patients received sofosbuvir and daclatasvir for 3 months (chronic hepatitis) and for 6 months in (liver cirrhosis). Results: Mean age of patients was 49.89 ± 9.01 years, 111 (55.5%) patients were male and 180 (90%) achieved SVR. Baseline IR had insignificant difference between responders and non-responders (93% v. 90%; P = 0.45), while baseline HOMA was significantly higher in non-responders (10.11 ± 3.03 vs. 8.48 ± 2.98; P = 0.01). Also, post-therapy IR had insignificant difference between both groups (73.3% vs. 85%; P = 0.05), while post-therapy HOMA was significantly higher in non-responders (7.12 ± 2.31 vs. 5.06 ± 1.34; P = 0.01). Predictors of non-responders were age (> 40 years), low serum albumin and post-therapy IR. Conclusion: Baseline IR had no impact on SVR but it showed significant improvement in presence of SVR.

Background & Aims Heavy alcohol consumption is a common cause of acute pancreatitis; however, alcohol abuse does not always result in clinical pancreatitis. As a consequence, the factors responsible for alcohol-induced pancreatitis are not well understood. In experimental animals, it has been difficult to produce pancreatitis with alcohol. Clinically, alcohol use predisposes to hypophosphatemia, and hypophosphatemia has been observed in some patients with acute pancreatitis. Because of abundant protein synthesis, the pancreas has high metabolic demands, and reduced mitochondrial function leads to organelle dysfunction and pancreatitis. We proposed, therefore, that phosphate deficiency might limit adenosine triphosphate synthesis and thereby contribute to alcohol-induced pancreatitis. Methods Mice were fed a low-phosphate diet (LPD) before orogastric administration of ethanol. Direct effects of phosphate and ethanol were evaluated in vitro in isolated mouse pancreatic acini. Results LPD reduced serum phosphate levels. Intragastric administration of ethanol to animals maintained on an LPD caused severe pancreatitis that was ameliorated by phosphate repletion. In pancreatic acinar cells, low-phosphate conditions increased susceptibility to ethanol-induced cellular dysfunction through decreased bioenergetic stores, specifically affecting total cellular adenosine triphosphate and mitochondrial function. Phosphate supplementation prevented ethanol-associated cellular injury. Conclusions Phosphate status plays a critical role in predisposition to and protection from alcohol-induced acinar cell dysfunction and the development of acute alcohol-induced pancreatitis. This finding may explain why pancreatitis develops in only some individuals with heavy alcohol use and suggests a potential novel therapeutic approach to pancreatitis. Finally, an LPD plus ethanol provides a new model for studying alcohol-associated pancreatic injury.

INTRODUCTION: Prognostic markers are needed to understand the disease course and severity in patients with Covid-19, a viral respiratory illness that causes systemic symptoms However, there is no model to date that evaluates the complexity of this illness We hypothesized that the MELD-Na score would be associated with disease severity in patients with Covid-19 METHODS: This is an IRB approved, retrospective, single institution, cohort study that analyzed patients admitted to a community academic hospital with the diagnosis of Covid-19 between March, 1st 2020 and June 11th, 2020 The primary outcome was mortality at 30 days based on MELD-Na score calculated at the time of admission Secondary outcomes included the development of an Acute Kidney Injury (AKI), need for hemodialysis (HD), need for vasopressor hemodynamic support, need for intubation and hospital stay lasting longer than 7 days RESULTS: The sample size consisted of 99 patients: admission data to calculate a MELD-Na score was available for 63 patients (63%) The MELD-Na score was found to be significantly higher in those who died at 30 days (14 38±6 92) after discharge relative to those who survived (9 68±5 69;P = 0 03);the odds of death at 30 days with a MELD-Na score greater than 10 was 9 00 (95% CI: 2 29, 35 50;P = 0 001) Patients with a MELD-Na score greater than 10 were more likely to have an AKI by an odds ratio (OR) of 3 31 (95% CI: 1 08, 10 17, P = 0 03), need HD by an OR of 9 69 (95% CI: 1 74, 53 96, P = 0 007), need vasopressor support by an OR of 4 55 (95% CI: 1 22, 16 99, P = 0 02) and stay in the hospital longer than 7 days by an OR of 4 17 (95% CI: 1 05, 16 47;P = 0 03) CONCLUSION: The MELD-Na score was found to be higher in patients with Covid-19 who died relative to those who survived at 30 days after discharge A MELD-Na score greater than 10 was prognostic of multiple clinical outcomes, including 30-day all cause mortality, development of an AKI, need for HD, need for vasopressors and longer hospital stay Thus, the MELD-Na score serves as a useful clinical scoring system for prognosis in patients admitted to the hospital with Covid-19 (Table Presented)

INTRODUCTION: Prognostic markers are needed to understand the disease course and severity in patients with Covid-19, a respiratory viral illness There is evidence that Covid-19 causes gastrointestinal symptoms and abnormalities in liver enzymes We aimed to determine if hepatobiliary laboratory data could predict disease severity in patients with Covid-19 METHODS: This is an IRB approved, retrospective, single institution, cohort study that analyzed patients admitted to a community academic hospital with the diagnosis of Covid-19 between March, 1st 2020 and May 5th, 2020 The primary outcome was the need for Intensive Care Unit (ICU) admission based on elevations in transaminases, Alkaline Phosphatase (AP) and Total Bilirubin (TB) Secondary outcomes included mortality, development of Acute Kidney Injury (AKI) or hypotension and need for supplemental oxygen RESULTS: Sixty patients were included in the analysis Elevation of Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) and Alkaline Phosphatase (AP) increased the odds of ICU admission by 5 12 (95% CI: 1 55,16 89;P = 0 007), 4 71 (95% CI: 1 51,14 69;P = 0 01) and 4 12 (95% CI: 1 21,14 06, P = 0 02), respectively Hypoalbuminemia was associated with increased mortality by an odds ratio of 6 79 (CI: 1 27-36 34, P = 0 02) Additionally, there was evidence of liver injury: the change in AST during admission above baseline was significantly higher in patients admitted to the ICU (54 2±15 70 U/L) relative to those who were not (9 2±4 89 U/L;P = 0 01) CONCLUSION: This study found that hypoalbuminemia and abnormalities in hepatobiliary laboratory data are prognostic factors for disease severity in patients admitted to the hospital with Covid-19 Additionally, there may be evidence of liver injury in Covid-19 patients that is more severe in those admitted to the ICU (Table Presented)

Background & Aims The NACHT, LRR, and pyrin domain–containing protein 3 (NLRP3) inflammasome induces inflammation in response to organ injury, but little is known about its regulation. Toll-like receptors (TLRs) provide the first signal required for activation of the inflammasome and stimulate aerobic glycolysis to generate lactate. We examined whether lactate and the lactate receptor, G i -protein–coupled receptor 81 (GPR81), regulate TLR induction of signal 1 and limit inflammasome activation and organ injury. Methods Primary mouse macrophages and human monocytes were incubated with TLR4 agonists and lactate and assayed for levels of pro-interleukin (IL)1β, NLRP3, and caspase-1 (CASP1); release of IL1β; and activation of nuclear factor-κB (NF-κB) and caspase-1. Small interfering RNAs were used to reduce levels of GPR81 and arrestin β-2 (ARRB2), and an NF-κB luciferase reporter transgene was transfected in RAW 264.7 cells. Cell lysates were analyzed by immunoprecipitation with an antibody against GPR81. Acute hepatitis was induced in C56BL/6N mice by administration of lipopolysaccharide and D-galactosamine. Acute pancreatitis was induced by administration of lipopolysaccharide and cerulein. Some mice were given intraperitoneal injections of sodium lactate or small interfering RNA against Gpr81. Activation of NF-κB in tissue macrophages was assessed in mice that expressed a reporter transgene. Results In macrophages and monocytes, increasing concentrations of lactate reduced TLR4-mediated induction of Il1B , Nlrp3 , and Casp1 ; activation of NF-κB; release of IL1β; and cleavage of CASP1. GPR81 and ARRB2 physically interacted and were required for these effects. The administration of lactate reduced inflammation and organ injury in mice with immune hepatitis; this reduction required Gpr81 dependence in vivo. Lactate also prevented activation of NF-κB in macrophages of mice, and, when given after injury, reduced the severity of acute pancreatitis and acute liver injury. Conclusions Lactate negatively regulates TLR induction of the NLRP3 inflammasome and production of IL1β, via ARRB2 and GPR81. Lactate could be a promising immunomodulatory therapy for patients with acute organ injury.

The ability of tissue injury to result in inflammation is a well-recognized phenomenon and is central to a number of common liver and pancreatic diseases including alcoholic steatohepatitis and pancreatitis, as well as drug-induced liver injury, non-alcoholic steatohepatitis, and pancreatitis from other causes. The requirements of extracellular damage-associated molecules and a cytosolic machinery labeled the inflammasome have been established in in vitro culture systems and in vivo disease models. This has provided a generic insight into the pathways involved, and the challenge now is to understand the specifics of these mechanisms in relation to the particular insults and organs involved. One reason for the excitement in this field is that a number of therapeutic candidates such a toll-like receptor antagonists and interleukin-1R antagonists are either approved or in clinical trials for other indications.

Question: A 60-yearold obese (body mass index of 50 kg/m2) woman was admitted through the emergency department with a history of severe colicky abdominal pain, abdominal distension, and constipation. She was known to have diverticular disease of sigmoid colon, hypertension, diabetes, and chronic obstructive pulmonary disease. here was no history of any previous abdominal operations. On examination, she was found to have distended abdomen with severe enderness and guarding in the left iliac fossa. Her bowel sounds were increased. She had an elevated white cell count (18,000/mm3) and normal liver function tests. Her plain abdominal film showed large bowel dilatation with cutoff in the sigmoid colon. With the clinical impression of large bowel obstruction with possible acute diverticulitis she underwent an emergency abdominal (Figure A) and pelvic (Figure B) computed tomography (CT). What is the complete diagnosis? Look on page 2279 for the answer and see the GASTROENTEROLOGY web site (www.gastrojournal.org) for more information n submitting your favorite image to Clinical Challenges and Images in GI. Conflicts of interest: The authors disclose no conflicts. © 2011 by the AGA Institute 0016-5085/$36.00 doi:10.1053/j.gastro.2010.11.042

Activation of the cytosolic inflammasome machinery is responsible for acute and chronic liver inflammation, but little is known about its regulation. The N-methyl-d-aspartate (NMDA) receptor families are heterotetrameric ligand-gated ion channels that are activated by a range of metabolites, including aspartate, glutamate, and polyunsaturated fatty acids. In the brain NMDA receptors are present on neuronal and nonneuronal cells and regulate a diverse range of functions. We tested the role of the NMDA receptor and aspartate in inflammasome regulation in vitro and in models of acute hepatitis and pancreatitis. We demonstrate that the NMDA receptor is present on Kupffer cells, and their activation on primary mouse and human cells limits inflammasome activation by downregulating NOD-like receptor family, pyrin domain containing 3 and procaspase-1. The NMDA receptor pathway is active in vivo, limits injury in acute hepatitis, and can be therapeutically further activated by aspartate providing protection in acute inflammatory liver injury. Downregulation of inflammasome activation by NMDA occurs via a β-arrestin-2 NF-kβ and JNK pathway and not via Ca2+ mobilization. We have identified the NMDA receptor as a regulator of inflammasome activity in vitro and in vivo. This has identified a new area of immune regulation associated by metabolites that may be relevant in a diverse range of conditions, including nonalcoholic steatohepatitis and total parenteral nutrition-induced immune suppression.