Acute pancreatitis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]; Tarek Nafee, M.D. [3]

Overview

The pathophysiology of acute pancreatitis involves acute inflammation and edema of the pancreas. The process is mediated by the abnormal activation of trypsinogen to trypsin inside the pancreas, and the involvement of other mediators such as cathepsin, lysosomal enzymes, and caspases. Intrapancreatic activation of amylase and lipase is what causes necrosis of pancreatic cells.

Pathophysiology

Pathogenesis

  • The two types of pancreatitis are mild pancreatitis and severe pancreatitis, which are separated based on whether their predominant response to cell injury is inflammation or necrosis, respectively.
  • In mild pancreatitis there is inflammation and edema of the pancreas.
  • In severe pancreatitis there are additional features of necrosis and secondary injury to extrapancreatic organs.
  • Both types share a common mechanism of abnormal inhibition of secretion of zymogens and inappropriate activation of pancreatic zymogens inside the pancreas, most notably trypsinogen. Normally, trypsinogen is activated to trypsin in the duodenum where it assists in the digestion of proteins.
  • During an acute pancreatitis episode there is co-localization of lysosomal enzymes, specifically cathepsin with trypsinogen.
  • Cathepsin activates trypsinogen to trypsin leading to further activation of other molecules of trypsinogen and immediate pancreatic cell death according to either the necrosis or apoptosis mechanism (or a mix between the two).
  • The balance between these two processes is mediated by caspases which regulate apoptosis and have important anti-necrosis functions during pancreatitis: preventing trypsinogen activation, preventing ATP depletion through inhibiting poly ADP-ribose polymerase, and by inhibiting the inhibitors of apoptosis (IAPs). If, however, the caspases are depleted due to either chronic ethanol exposure or through a severe insult then necrosis can predominate.

Transient Obstruction of Pancreatic Ducts

  • The aforementioned inflammatory process which primarily manifests as oversecretion of zymogens and activation of trypsinogen in the pancreas is often a result of transient obstruction of the pancreatic ducts.
  • This obstruction is the triggering insult which is the underlying mechanism for the most common cause of acute pancreatitis - migrating gallstones or sludge.
  • Other causes of transient obstruction include:
    • Dysfunctional sphincter of Oddi
    • Pancreas divisium, though the association of these disorders with acute pancreatitis has come into question in the absence of underlying genetic disease.[1]

[2]

Alcoholism

  • Alcohol is proposed to have a direct toxic effect on the pancreas.
  • It is metabolized by the pancreas and may result in oxidative stress and induce the release of pancreatic enzymes. This excessive release may result in auto-digestion of the gland.
  • Additionally, alcohol may result in activation of pancreatic stellate cells which are primarily responsible for fibrosis of the gland and weakening of the intracellular membranes, which results in anatomical changes in the pancreas, further predisposing to pathological auto-digestion.[3][2]

Hypertriglyceridemia

Post ERCP Pancreatitis

  • The mechanism by which post-ERCP pancreatitis (PEP) occurs is not fully understood.
  • However, it is proposed that mechanical, chemical, allergic, and thermally induced trauma to the pancreatic orifice and duct are the underlying causes.
  • Instrumental manipulation of the pancreatic orifices, as well as chemical and allergic damage due to contrast injection contribute to the pathogenesis.[7][8]
  • Additionally, cauterization of the superficial and intraluminal pancreatic structures may result in thermal damage.[9]
  • These iatrogenic traumatic and toxic influences may, again, stimulate the fibrogenic pancreatic stellate cells to initiate a cascade of events responsible for activation of zymogens and autodigestion of the pancreas.[10][11][2]

Microscopic Pathology

Genetics

Several genes have been proposed to play a role in the pathogenesis of acute pancreatitis. While the exact role of every implicated genetic mutation is not fully understood, the following genes have been associated with the development of acute pancreatitis:[12][2]

Associated Conditions

The most common conditions associated with acute pancreatitis include:[2]

References

  1. Coté GA, Imperiale TF, Schmidt SE, Fogel E, Lehman G, McHenry L; et al. (2012). "Similar efficacies of biliary, with or without pancreatic, sphincterotomy in treatment of idiopathic recurrent acute pancreatitis". Gastroenterology. 143 (6): 1502–1509.e1. doi:10.1053/j.gastro.2012.09.006. PMID 22982183.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 Forsmark CE, Vege SS, Wilcox M (November 17,2016). "Acute Pancreatitis". The New England Journal of Medicine: 1972–1981. doi:10.1056/NEJMra1505202. Retrieved November 25,2016. Check date values in: |access-date=, |date= (help)
  3. Apte MV, Pirola RC, Wilson JS (2010). "Mechanisms of alcoholic pancreatitis". J Gastroenterol Hepatol. 25 (12): 1816–26. doi:10.1111/j.1440-1746.2010.06445.x. PMID 21091991.
  4. Kota SK, Kota SK, Jammula S, Krishna SV, Modi KD (2012). "Hypertriglyceridemia-induced recurrent acute pancreatitis: A case-based review". Indian J Endocrinol Metab. 16 (1): 141–3. doi:10.4103/2230-8210.91211. PMC 3263185. PMID 22276267.
  5. Yadav D, Pitchumoni CS (2003). "Issues in hyperlipidemic pancreatitis". J Clin Gastroenterol. 36 (1): 54–62. PMID 12488710.
  6. Kimura W, Mössner J (1996). "Role of hypertriglyceridemia in the pathogenesis of experimental acute pancreatitis in rats". Int J Pancreatol. 20 (3): 177–84. doi:10.1007/BF02803766. PMID 9013278.
  7. Sherman S (1994). "ERCP and endoscopic sphincterotomy-induced pancreatitis". Am J Gastroenterol. 89 (3): 303–5. PMID 8122635.
  8. George S, Kulkarni AA, Stevens G, Forsmark CE, Draganov P (2004). "Role of osmolality of contrast media in the development of post-ERCP pancreatitis: a metanalysis". Dig Dis Sci. 49 (3): 503–8. PMID 15139506.
  9. Ratani RS, Mills TN, Ainley CC, Swain CP (1999). "Electrophysical factors influencing endoscopic sphincterotomy". Gastrointest Endosc. 49 (1): 43–52. PMID 9869722.
  10. Baillie J (2011). "Management of Post-ERCP Pancreatitis". Gastroenterol Hepatol (N Y). 7 (6): 390–2. PMC 3151411. PMID 21869870.
  11. Matsubayashi H, Fukutomi A, Kanemoto H, Maeda A, Matsunaga K, Uesaka K; et al. (2009). "Risk of pancreatitis after endoscopic retrograde cholangiopancreatography and endoscopic biliary drainage". HPB (Oxford). 11 (3): 222–8. doi:10.1111/j.1477-2574.2008.00020.x. PMC 2697892. PMID 19590651.
  12. Whitcomb DC (2013). "Genetic risk factors for pancreatic disorders". Gastroenterology. 144 (6): 1292–302. doi:10.1053/j.gastro.2013.01.069. PMC 3684061. PMID 23622139.
  13. Coté GA, Yadav D, Slivka A, Hawes RH, Anderson MA, Burton FR; et al. (2011). "Alcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis". Clin Gastroenterol Hepatol. 9 (3): 266–73, quiz e27. doi:10.1016/j.cgh.2010.10.015. PMC 3043170. PMID 21029787.
  14. Coté GA, Yadav D, Slivka A, Hawes RH, Anderson MA, Burton FR; et al. (2011). "Alcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis". Clin Gastroenterol Hepatol. 9 (3): 266–73, quiz e27. doi:10.1016/j.cgh.2010.10.015. PMC 3043170. PMID 21029787.
  15. Hong S, Qiwen B, Ying J, Wei A, Chaoyang T (2011). "Body mass index and the risk and prognosis of acute pancreatitis: a meta-analysis". Eur J Gastroenterol Hepatol. 23 (12): 1136–43. doi:10.1097/MEG.0b013e32834b0e0e. PMID 21904207.



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