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Recent advances in basic science
Critical thresholds: key to unlocking the door to the prevention and specific treatments for acute pancreatitis
  1. Savio George Barreto1,2,
  2. Aida Habtezion3,
  3. Anna Gukovskaya4,5,
  4. Aurelia Lugea6,
  5. Christie Jeon6,
  6. Dhiraj Yadav7,
  7. Peter Hegyi8,9,10,
  8. Viktória Venglovecz11,
  9. Robert Sutton12,
  10. Stephen J Pandol6
  1. 1 Division of Surgery and Perioperative Medicine, Flinders Medical Center, Bedford Park, Adelaide, South Australia, Australia
  2. 2 College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
  3. 3 Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
  4. 4 Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA
  5. 5 Department of Medicine, West Los Angeles VA Healthcare Center, Los Angeles, California, USA
  6. 6 Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California, USA
  7. 7 Division of Gastroenterology & Hepatology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
  8. 8 First Department of Medicine, Faculty of Medicine, University of Szeged, Szeged, Hungary
  9. 9 Institute for Translational Medicine and First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
  10. 10 Szentágothai Research Center, University of Pécs, Pécs, Hungary
  11. 11 Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
  12. 12 Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
  1. Correspondence to Dr Stephen J Pandol, Basic and Translational Pancreatic Research, Cedars Sinai Medical Center, Los Angeles, California, USA; Stephen.Pandol{at}cshs.org

Abstract

Acute pancreatitis (AP), an acute inflammatory disorder of the exocrine pancreas, is one of the most common gastrointestinal diseases encountered in emergency departments with no specific treatments. Laboratory-based research has formed the cornerstone of endeavours to decipher the pathophysiology of AP, because of the limitations of such study in human beings. While this has provided us with substantial understanding, we cannot answer several pressing questions. These are: (a) Why is it that only a minority of individuals with gallstones, or who drink alcohol excessively, or are exposed to other causative factors develop AP? (b) Why do only some develop more severe manifestations of AP with necrosis and/or organ failure? (c) Why have we been unable to find an effective therapeutic for AP? This manuscript provides a state-of-the-art review of our current understanding of the pathophysiology of AP providing insights into the unanswered clinical questions. We describe multiple protective factors operating in most people, and multiple stressors that in a minority induce AP, independently or together, via amplification loops. We present testable hypotheses aimed at halting progression of severity for the development of effective treatments for this common unpredictable disease.

  • acute pancreatitis
  • epidemiology
  • pancreatic islet cell
  • pancreatic disorders
  • pancreatic secretion

https://doi.org/10.1136/gutjnl-2020-322163

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    Footnotes

    • Correction notice This article has been corrected since it published Online First. All author affiliations have been updated.

    • Contributors SGB: conceptualisation and design, literature search, drafting the manuscript and final approval. AH, AL, AG, CJ, DY, PH, VV and RS: literature search, drafting the manuscript, critical revision of manuscript and final approval. SJP: design of the study, literature search, critical revision of manuscript and final approval.

    • Funding DY support—UO1 DK108306; DoD PR182623. PH and VV support—National Research, Development and Innovation Office project grants (FK123982 to VV and K131996 to PH). PH support—GINOP 2.3.2-15-2016-00048 STAY ALIVE (PH). SJP support—US NIH: R01 AA024464, P01 DK098108, P50 AA0119991, U01 DK108314 US DoD: W81XWH1910888. RS support—funded by the U.K. Medical Research Council and National Institute for Health Research (EME 15/20/01), European Union Innovative Medicines Initiative, GlaxoSmithKline PLC and Hampson Trust, and is an NIHR Senior Investigator. AH support—NIH U01 DK108300, NIH DK092421 and DOD W81XWH-17-1-0339. CJ support—U01DK108314, DoD: W81XWH1910888.

    • Competing interests RS has received research support and/or funding from Calcimedica, Cypralis, GlaxoSmithKline, MSD/Merck and Novartis, has been a consultant for AbbVie, Calcimedica, Cypralis, Eagle Pharmaceuticals, Novartis and Takeda (all funds to the University of Liverpool), and is collaborating in the IMI2 TransBioLine project with multiple public and private institutions including Janssen, Lilly, MSD/Merck, Novartis, Pfizer, Roche and Sanofi-Aventis.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.