Chronic pancreatitis pathophysiology

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Overview

Pathophysiology

By Robert Jaster [CC BY 2.0 (http://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons
Source: nih.gov
  • Chronic pancreatitis is a progressive inflammatory process leading to irreversible structural damage to pancreas resulting in exocrine and endocrine dysfunction[1]
  • The pathogenesis is still unclear and multifactorial; but two mechanisms that play an important role in the pathogenesis of chronic pancreatitis are:

Decreased Bicarbonate secretion:

  • Protein hypersecretion resulting in proteinaceous ductal plugs leading to ductal blockage and obstruction[2]

Intrapancreatic activation of digestive enzymes:

  • Usually results from genetic causes leading to
    • Impaired enzyme activation and regulation
    • Predisposition to injury from toxic environmental stimuli such as alcohol or cigarette smoking

Other factors that are thought to play an important role in the pathogenesis of chronic pancreatitis:

(a) Intraductal plugging and obstruction

1) Proteinaceous ductal plugs
  • Interlobular and intralobular duct blockage due to abnormal secretion of pancreatic proteins in the pancreatic juice[2]
    • GP2, a glycosyl phosphatidylinositol anchored protein is found to be a major component of plugs.[3]
    • Low levels of lithostathine in alcoholics, a protective protein secreted by pancreatic acinar cells that prevent stone (calcium carbonate) formation.[4]
  • These proteinaceous plugs are the major sites for calcification and stone formation leading to:
    • Ductal epithelial lesions and inflammatory changes
    • Scarring
    • Obstruction
2) Intraductal obstruction due to other causes
  • Chronic exposure to stones results in damage to ductal epithelial cells and acinar glands via
    • Ulceration
    • Scarring
    • Obstruction
  • Biliaropancreatic tumors (pancreatic adenocarcinoma, neuroendocrine tumors, and intrapapillary mucinous tumors)
  • Ethanol abuse
    • Alcohol may increase the lithogenecity of pancreatic juice resulting in increased stone formation.

(b) Direct injury to pancreatic cells induced by toxins and toxic metabolites

  • Alcohol is proposed to have a direct toxic effect on the pancreas and damage the acinar cells via a change in intracellular metabolism.
  • 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 autodigestion 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 autodigestion.[5][6]
  • Smoking may exacerbate pancreatitis in alcoholics. It is also found as an independent risk factor in the development and progression of pancreatitis as:
    • It may affect pancreatic bicarbonate and water secretion
    • It may predispose to oxidative stress
    • It may also increases the rate of pancreatic calcification.

(c) Antioxidants

  • Steatorrhea in chronic pancreatitis may lead to nutritional deficiencies and decreased levels of antioxidants such as[7][8]
    • Selenium
    • Vitamin C and E
    • Methionine
  • Decreased antioxidant levels may result in:[9][10][11]
    • Increased free radical formation
    • Lipid peroxidation
    • Cellular damage

(d) Ischemia

  • Ischemia is an important precipitating factor in the pathogenesis of chronic pancreatitis
  • Fibrosis and inelasticity of pancreatic tissue seen in chronic pancreatitis may lead to:
    • Increased pancreatic interstitial pressure
    • Increased intraductal pressure and ductal hypertension[12]
    • Chronic ischemia and necrosis of pancreatic gland[13]

(e) Autoimmune disorders

  • Chronic pancreatitis is found to be associated with autoimmune conditions such as:[14][15]
    • Sjögren's syndrome
    • Primary biliary cirrhosis
    • Renal tubular acidosis 
  • HLA-DR antigen expression with T-cell inflammatory infiltrate is seen on duct cells in some cases of idiopathic chronic pancreatitis.[16]

(f) Necrosis and fibrosis

  • Recurrent attacks of acute pancreatitis may lead to chronic pancreatitis due to[17][18]
    • Necrosis
    • Fibrosis
    • Scarring of pancreatic gland
    • Intrinsic compression of the pancreatic ductules
  • Progression from acute to chronic pancreatitis is dependent upon the number and severity of acute attacks.[19]

(g) The sentinal acute pancreatitis event (SAPE) hypothesis:

  • This hypothesis explains the role of  pancreatic stellate cells in chronic pancreatitis[17][20]
  • It explains the pathogenesis of chronic pancreatitis on a continuum of 3 sequential changes
    • Pre acute pancreatitis; it is based on the assumption that chronic pancreatitis occurs in genetically or environmentally susceptible people or who are at increased risk.
    • The sentinel attack of acute pancreatitis; This stage involves
      • Triggering of chronic inflammation in the predisposed patients
      • Activation and recruitment of stellate cells
    • Progression phase; The immune system activation ultimately results in
      • Progression of inflammation
      • Irreversible changes

Genetics

Genes involved in the pathogenesis of chronic pancreatitis include:

  • CFTR-Cystic fibrosis gene mutation[21][22]
  • SPINK-1, which encodes for trypsin inhibitor[23]
  • PRSS-1 gene linked to hereditary pancreatitis
  • Claudin-2 (CLDN2)[24]
  • Carboxypeptidase A1 (CPA1) genes[25]

Associated Conditions

  • Autoimmune conditions
    • Primary biliary cirrhosis
    • Primary sclerosing cholangitis
    • Sjögren syndrome
    • Renal tubular acidosis

Gross Pathology

  • On gross examination, following findings may be observed:
    • Enlarged or atrophic pancreas
    • Cysts
    • Calcifications
    • Fibrosis
    • Patchy focal necrosis
By Dr. Roshan Nasimudeen [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons
By Dr. Roshan Nasimudeen [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons
Case courtesy of Dr Henry Knipe, <a href="https://radiopaedia.org/">Radiopaedia.org</a>. From the case <a href="https://radiopaedia.org/cases/27870">rID: 27870</a>
Case courtesy of Dr Henry Knipe, <a href="https://radiopaedia.org/">Radiopaedia.org</a>. From the case <a href="https://radiopaedia.org/cases/27870">rID: 27870</a>

Microscopic Pathology

  • On microscopic histopathological analysis:
    • Patchy focal disease characterized by a mononuclear infiltrate
  • Early phase findings:
    • Increased amount of peri-ductal and inter-lobular connective tissue
    • Minimal to moderate degree of inflammation (mostly T lymphocyte)
    • The islets of Langerhans are relatively spared
  • Late phase findings:
    • Increased amount of connective tissue between the acini causing their distortion and disappearance
    • Connective tissue is replaced by fibrous tissue
    • Involvement of the islets of Langerhans
  • Pancreatic lipomatosis may also be seen. It can be:
    • Even
    • Uneven
Type Uneven pancreatic lipomatosis
Type 1a Preferential fatty replacement of head
Type 1b Preferential fatty replacement of head, neck and body
Type 2a Preferential fatty replacement of head and uncinate process
Type 2b Fatty replacement of most of pancreas except peribiliary region
By Patho - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=29668664
By Patho - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=29668789

References

  1. Steer ML, Waxman I, Freedman S (1995). "Chronic pancreatitis". N. Engl. J. Med. 332 (22): 1482–90. doi:10.1056/NEJM199506013322206. PMID 7739686.
  2. 2.0 2.1 Sahel J, Sarles H (1979). "Modifications of pure human pancreatic juice induced by chronic alcohol consumption". Dig. Dis. Sci. 24 (12): 897–905. PMID 510088.
  3. Freedman SD, Sakamoto K, Venu RP (1993). "GP2, the homologue to the renal cast protein uromodulin, is a major component of intraductal plugs in chronic pancreatitis". J. Clin. Invest. 92 (1): 83–90. doi:10.1172/JCI116602. PMC 293537. PMID 8326020.
  4. Guy O, Robles-Diaz G, Adrich Z, Sahel J, Sarles H (1983). "Protein content of precipitates present in pancreatic juice of alcoholic subjects and patients with chronic calcifying pancreatitis". Gastroenterology. 84 (1): 102–7. PMID 6401181.
  5. 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.
  6. 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)
  7. Rose P, Fraine E, Hunt LP, Acheson DW, Braganza JM (1986). "Dietary antioxidants and chronic pancreatitis". Hum Nutr Clin Nutr. 40 (2): 151–64. PMID 3957720.
  8. Uden S, Acheson DW, Reeves J, Worthington HV, Hunt LP, Brown S, Braganza JM (1988). "Antioxidants, enzyme induction, and chronic pancreatitis: a reappraisal following studies in patients on anticonvulsants". Eur J Clin Nutr. 42 (7): 561–9. PMID 3224602.
  9. Braganza JM, Thomas A, Robinson A (1988). "Antioxidants to treat chronic pancreatitis in childhood? Case report and possible implications for pathogenesis". Int. J. Pancreatol. 3 (2–3): 209–16. doi:10.1007/BF02798933. PMID 3361161.
  10. Bhardwaj P, Garg PK, Maulik SK, Saraya A, Tandon RK, Acharya SK (2009). "A randomized controlled trial of antioxidant supplementation for pain relief in patients with chronic pancreatitis". Gastroenterology. 136 (1): 149–159.e2. doi:10.1053/j.gastro.2008.09.028. PMID 18952082.
  11. Burton F, Alkaade S, Collins D, Muddana V, Slivka A, Brand RE, Gelrud A, Banks PA, Sherman S, Anderson MA, Romagnuolo J, Lawrence C, Baillie J, Gardner TB, Lewis MD, Amann ST, Lieb JG, O'Connell M, Kennard ED, Yadav D, Whitcomb DC, Forsmark CE (2011). "Use and perceived effectiveness of non-analgesic medical therapies for chronic pancreatitis in the United States". Aliment. Pharmacol. Ther. 33 (1): 149–59. doi:10.1111/j.1365-2036.2010.04491.x. PMC 3142582. PMID 21083584.
  12. Karanjia ND, Singh SM, Widdison AL, Lutrin FJ, Reber HA (1992). "Pancreatic ductal and interstitial pressures in cats with chronic pancreatitis". Dig. Dis. Sci. 37 (2): 268–73. PMID 1735346.
  13. Tanaka T, Ichiba Y, Miura Y, Ito H, Dohi K (1994). "Canine model of chronic pancreatitis due to chronic ischemia". Digestion. 55 (2): 86–9. PMID 7514552.
  14. Epstein O, Chapman RW, Lake-Bakaar G, Foo AY, Rosalki SB, Sherlock S (1982). "The pancreas in primary biliary cirrhosis and primary sclerosing cholangitis". Gastroenterology. 83 (6): 1177–82. PMID 7129026.
  15. Nishimori I, Yamamoto Y, Okazaki K, Morita M, Onodera M, Kino J, Tamura S, Yamamoto Y (1994). "Identification of autoantibodies to a pancreatic antigen in patients with idiopathic chronic pancreatitis and Sjögren's syndrome". Pancreas. 9 (3): 374–81. PMID 8022761.
  16. Bovo P, Mirakian R, Merigo F, Angelini G, Cavallini G, Rizzini P, Bottazzo GF, Scuro LA (1987). "HLA molecule expression on chronic pancreatitis specimens: is there a role for autoimmunity? A preliminary study". Pancreas. 2 (3): 350–6. PMID 3498162.
  17. 17.0 17.1 Schneider A, Whitcomb DC (2002). "Hereditary pancreatitis: a model for inflammatory diseases of the pancreas". Best Pract Res Clin Gastroenterol. 16 (3): 347–63. doi:10.1053/bega.2002.0311. PMID 12079262.
  18. Lankisch PG, Breuer N, Bruns A, Weber-Dany B, Lowenfels AB, Maisonneuve P (2009). "Natural history of acute pancreatitis: a long-term population-based study". Am. J. Gastroenterol. 104 (11): 2797–805, quiz 2806. doi:10.1038/ajg.2009.405. PMID 19603011.
  19. Ammann RW, Muellhaupt B (1994). "Progression of alcoholic acute to chronic pancreatitis". Gut. 35 (4): 552–6. PMC 1374808. PMID 8174996.
  20. Yadav D, Whitcomb DC (2010). "The role of alcohol and smoking in pancreatitis". Nat Rev Gastroenterol Hepatol. 7 (3): 131–45. doi:10.1038/nrgastro.2010.6. PMID 20125091.
  21. Bishop MD, Freedman SD, Zielenski J, Ahmed N, Dupuis A, Martin S, Ellis L, Shea J, Hopper I, Corey M, Kortan P, Haber G, Ross C, Tzountzouris J, Steele L, Ray PN, Tsui LC, Durie PR (2005). "The cystic fibrosis transmembrane conductance regulator gene and ion channel function in patients with idiopathic pancreatitis". Hum. Genet. 118 (3–4): 372–81. doi:10.1007/s00439-005-0059-z. PMID 16193325.
  22. Ooi CY, Gonska T, Durie PR, Freedman SD (2010). "Genetic testing in pancreatitis". Gastroenterology. 138 (7): 2202–6, 2206.e1. doi:10.1053/j.gastro.2010.04.022. PMID 20416310.
  23. Witt H, Luck W, Hennies HC, Classen M, Kage A, Lass U, Landt O, Becker M (2000). "Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis". Nat. Genet. 25 (2): 213–6. doi:10.1038/76088. PMID 10835640.
  24. Whitcomb DC, LaRusch J, Krasinskas AM, Klei L, Smith JP, Brand RE, Neoptolemos JP, Lerch MM, Tector M, Sandhu BS, Guda NM, Orlichenko L, Alkaade S, Amann ST, Anderson MA, Baillie J, Banks PA, Conwell D, Coté GA, Cotton PB, DiSario J, Farrer LA, Forsmark CE, Johnstone M, Gardner TB, Gelrud A, Greenhalf W, Haines JL, Hartman DJ, Hawes RA, Lawrence C, Lewis M, Mayerle J, Mayeux R, Melhem NM, Money ME, Muniraj T, Papachristou GI, Pericak-Vance MA, Romagnuolo J, Schellenberg GD, Sherman S, Simon P, Singh VP, Slivka A, Stolz D, Sutton R, Weiss FU, Wilcox CM, Zarnescu NO, Wisniewski SR, O'Connell MR, Kienholz ML, Roeder K, Barmada MM, Yadav D, Devlin B (2012). "Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis". Nat. Genet. 44 (12): 1349–54. doi:10.1038/ng.2466. PMC 3510344. PMID 23143602.
  25. Witt H, Beer S, Rosendahl J, Chen JM, Chandak GR, Masamune A, Bence M, Szmola R, Oracz G, Macek M, Bhatia E, Steigenberger S, Lasher D, Bühler F, Delaporte C, Tebbing J, Ludwig M, Pilsak C, Saum K, Bugert P, Masson E, Paliwal S, Bhaskar S, Sobczynska-Tomaszewska A, Bak D, Balascak I, Choudhuri G, Nageshwar Reddy D, Rao GV, Thomas V, Kume K, Nakano E, Kakuta Y, Shimosegawa T, Durko L, Szabó A, Schnúr A, Hegyi P, Rakonczay Z, Pfützer R, Schneider A, Groneberg DA, Braun M, Schmidt H, Witt U, Friess H, Algül H, Landt O, Schuelke M, Krüger R, Wiedenmann B, Schmidt F, Zimmer KP, Kovacs P, Stumvoll M, Blüher M, Müller T, Janecke A, Teich N, Grützmann R, Schulz HU, Mössner J, Keim V, Löhr M, Férec C, Sahin-Tóth M (2013). "Variants in CPA1 are strongly associated with early onset chronic pancreatitis". Nat. Genet. 45 (10): 1216–20. doi:10.1038/ng.2730. PMC 3909499. PMID 23955596.


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