Chronic pancreatitis pathophysiology: Difference between revisions
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==== (e) Autoimmune disorders ==== | ==== (e) Autoimmune disorders ==== | ||
* Chronic pancreatitis is found to be associated with autoimmune conditions such as: | * Chronic pancreatitis is found to be associated with autoimmune conditions such as:<ref name="pmid7129026">{{cite journal |vauthors=Epstein O, Chapman RW, Lake-Bakaar G, Foo AY, Rosalki SB, Sherlock S |title=The pancreas in primary biliary cirrhosis and primary sclerosing cholangitis |journal=Gastroenterology |volume=83 |issue=6 |pages=1177–82 |year=1982 |pmid=7129026 |doi= |url=}}</ref><ref name="pmid8022761">{{cite journal |vauthors=Nishimori I, Yamamoto Y, Okazaki K, Morita M, Onodera M, Kino J, Tamura S, Yamamoto Y |title=Identification of autoantibodies to a pancreatic antigen in patients with idiopathic chronic pancreatitis and Sjögren's syndrome |journal=Pancreas |volume=9 |issue=3 |pages=374–81 |year=1994 |pmid=8022761 |doi= |url=}}</ref> | ||
** Sjögren's syndrome | ** Sjögren's syndrome | ||
** Primary biliary cirrhosis | ** Primary biliary cirrhosis | ||
** Renal tubular acidosis | ** Renal tubular acidosis | ||
* | * | ||
==== (f) Necrosis and fibrosis ==== | ==== (f) Necrosis and fibrosis ==== | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Overview
Pathophysiology
- 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 but two findings consistently seen in the pathogenesis of chronic pancreatitis are:
- Protein hypersecretion resulting in proteinaceous ductal plugs leading to ductal blockage and obstruction[2]
- Patchy inflammatory lesions in exocrine pancreas seen on microscopic examination
Following factors 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]
- These proteinaceous plugs are the major sites for calification and stone formation leading to
- Ductal epithelial lesions and inflammatory changes
- Scarring
- Obstruction
2) Intraductal obstruction due to other causes
- Stones
- Tumors
- Ethanol abuse
(b) Direct injury to pancreatic cells induced by toxins and toxic metabolites
- 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 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]
(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:
(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
(f) Necrosis and fibrosis
Genetics
Genes involved in the pathogenesis of chronic pancreatitis include:
- CFTR-Cystic fibrosis gene mutation[16][17]
- SPINK-1, which encodes for trypsin inhibitor[18]
- PRSS-1 gene linked to hereditary pancreatitis
- Claudin-2 (CLDN2)[19]
- Carboxypeptidase A1 (CPA1) genes[20]
Associated Conditions
- Autoimmune conditions
- Primary biliary cirrhosis
- Primary sclerosing cholangitis
- Sjögren syndrome
- Renal tubular acidosis
Gross Pathology
- Patchy focal necrosis
- Fibrosis
- Small, hard and shrinked pancreas
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
References
- ↑ Steer ML, Waxman I, Freedman S (1995). "Chronic pancreatitis". N. Engl. J. Med. 332 (22): 1482–90. doi:10.1056/NEJM199506013322206. PMID 7739686.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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) - ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.