Chronic pancreatitis pathophysiology
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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
(d) Ischemia
(e) Autoimmune disorders
(f) Necrosis and fibrosis
Genetics
Genes involved in the pathogenesis of chronic pancreatitis include:
- CFTR-Cystic fibrosis gene mutation[7][8]
- SPINK-1, which encodes for trypsin inhibitor[9]
- PRSS-1 gene linked to hereditary pancreatitis
- Claudin-2 (CLDN2)
- Carboxypeptidase A1 (CPA1) genes
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) - ↑ 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.