Hereditary pancreatitis pathophysiology: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
 
(21 intermediate revisions by 2 users not shown)
Line 4: Line 4:
{{CMG}}; {{AE}}{{IQ}}
{{CMG}}; {{AE}}{{IQ}}
==Overview==
==Overview==
Hereditary pancreatitis is caused by genetic mutations in the regulatory regions present on trypsin. Mutations in [[PRSS16|PRSS1]], ''[[SPINK1]]'', ''[https://en.wikipedia.org/wiki/Chymotrypsin-C CTRC]'', and ''[[CFTR]]'' gene result in weakening of defense mechanisms against pancreatitis. Defense mechanisms against pancreatitis include control of [[trypsin]] activity via prevention of premature activation of [[trypsinogen]] to [[trypsin]] and destruction, inhibition, or elimination of [[trypsin]] from the pancreas. Premature activation of digestive enzymes resulting in pancreatic injury, [[immune system]] activation, acute pancreatitis, and chronic pancreatitis. Hereditary pancreatitis may be associated with [[Shwachman-Diamond syndrome]] (SDS), Pearson marrow pancreas syndrome, CEL maturity-onset diabetes of the young (''CEL''-MODY) and [[Johanson-Blizzard syndrome]]. Gross examination may show enlarged or [[atrophic]] pancreas, [[cysts]], [[calcification|calcifications]] and [[fibrosis]]. On microscopic histopathological analysis, non-invasive dysplastic intraductal lesions, called pancreatic intraepithelial neoplasia (PanIN), may be noticed.


==Pathophysiology==
==Pathophysiology==
Line 13: Line 14:


==== Regulatory regions of trypsin: ====
==== Regulatory regions of trypsin: ====
* There are two regulatory regions present on trypsin.
* There are two regulatory regions present on [[trypsin]]
* Almost all of the genetic mutations associated with hereditary pancreatitis are clustered in these 2 regulatory regions.
* Almost all of the genetic mutations associated with hereditary pancreatitis are clustered in these 2 regulatory regions


===== (a) Regulatory region on the activation site =====
===== (a) Regulatory region on the activation site =====
* It regulates the activation site.
* It regulates the activation site
* It converts trypsinogen into trypsin.
* It converts trypsinogen into [[trypsin]]


===== (b)  Regulatory region on the autolysis site =====
===== (b)  Regulatory region on the autolysis site =====
* It regulates the autolysis site.
* It regulates the autolysis site
*  It causes destruction of trypsin.
*  It causes destruction of [[trypsin]]


==== Abnormal regulation of trypsin: ====
==== Abnormal regulation of trypsin: ====
*Mutations in PRSS1, ''SPINK1'', ''CTRC'', and ''CFTR'' gene result in weakening of defense mechanisms against pancreatitis.<ref name="pmid20059346">{{cite journal |vauthors=Whitcomb DC |title=Genetic aspects of pancreatitis |journal=Annu. Rev. Med. |volume=61 |issue= |pages=413–24 |year=2010 |pmid=20059346 |doi=10.1146/annurev.med.041608.121416 |url=}}</ref> <ref name="pmid10381903">{{cite journal |vauthors=Witt H, Luck W, Becker M |title=A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis |journal=Gastroenterology |volume=117 |issue=1 |pages=7–10 |year=1999 |pmid=10381903 |doi= |url=}}</ref><ref name="pmid10406366">{{cite journal |vauthors=Creighton J, Lyall R, Wilson DI, Curtis A, Charnley R |title=Mutations of the cationic trypsinogen gene in patients with chronic pancreatitis |journal=Lancet |volume=354 |issue=9172 |pages=42–3 |year=1999 |pmid=10406366 |doi=10.1016/S0140-6736(99)01814-0 |url=}}</ref>
*Mutations in [[PRSS16|PRSS1]], ''[[SPINK1]]'', ''[https://en.wikipedia.org/wiki/Chymotrypsin-C CTRC]'', and ''[[CFTR gene|CFTR]]'' gene result in weakening of defense mechanisms against pancreatitis.<ref name="pmid20059346">{{cite journal |vauthors=Whitcomb DC |title=Genetic aspects of pancreatitis |journal=Annu. Rev. Med. |volume=61 |issue= |pages=413–24 |year=2010 |pmid=20059346 |doi=10.1146/annurev.med.041608.121416 |url=}}</ref> <ref name="pmid10381903">{{cite journal |vauthors=Witt H, Luck W, Becker M |title=A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis |journal=Gastroenterology |volume=117 |issue=1 |pages=7–10 |year=1999 |pmid=10381903 |doi= |url=}}</ref><ref name="pmid10406366">{{cite journal |vauthors=Creighton J, Lyall R, Wilson DI, Curtis A, Charnley R |title=Mutations of the cationic trypsinogen gene in patients with chronic pancreatitis |journal=Lancet |volume=354 |issue=9172 |pages=42–3 |year=1999 |pmid=10406366 |doi=10.1016/S0140-6736(99)01814-0 |url=}}</ref>
*Defense mechanisms against pancreatitis include control of trypsin activity via:
*Defense mechanisms against pancreatitis include control of [[trypsin]] activity via:
**Prevention of premature activation of trypsinogen to trypsin.
**Prevention of premature activation of [[trypsinogen]] to [[trypsin]]
**Destruction, inhibition, or elimination of trypsin from the pancreas.
**Destruction, inhibition, or elimination of [[trypsin]] from the pancreas  


==== Mutations at different sites on PRSS1 gene: ====
==== Mutations at different sites on PRSS1 gene: ====
* New mutations at different sites on PRSS1 gene may include:<ref name="pmid10381903">{{cite journal |vauthors=Witt H, Luck W, Becker M |title=A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis |journal=Gastroenterology |volume=117 |issue=1 |pages=7–10 |year=1999 |pmid=10381903 |doi= |url=}}</ref><ref name="pmid19191323">{{cite journal |vauthors=Kereszturi E, Szmola R, Kukor Z, Simon P, Weiss FU, Lerch MM, Sahin-Tóth M |title=Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism |journal=Hum. Mutat. |volume=30 |issue=4 |pages=575–82 |year=2009 |pmid=19191323 |pmc=2663013 |doi=10.1002/humu.20853 |url=}}</ref><ref name="pmid10514442">{{cite journal |vauthors=Sahin-Tóth M |title=Hereditary pancreatitis-associated mutation asn(21) --> ile stabilizes rat trypsinogen in vitro |journal=J. Biol. Chem. |volume=274 |issue=42 |pages=29699–704 |year=1999 |pmid=10514442 |doi= |url=}}</ref><ref name="pmid10930381">{{cite journal |vauthors=Teich N, Ockenga J, Hoffmeister A, Manns M, Mössner J, Keim V |title=Chronic pancreatitis associated with an activation peptide mutation that facilitates trypsin activation |journal=Gastroenterology |volume=119 |issue=2 |pages=461–5 |year=2000 |pmid=10930381 |doi= |url=}}</ref><ref name="pmid11866271">{{cite journal |vauthors=Teich N, Bauer N, Mössner J, Keim V |title=Mutational screening of patients with nonalcoholic chronic pancreatitis: identification of further trypsinogen variants |journal=Am. J. Gastroenterol. |volume=97 |issue=2 |pages=341–6 |year=2002 |pmid=11866271 |doi=10.1111/j.1572-0241.2002.05467.x |url=}}</ref><ref name="pmid19951905">{{cite journal |vauthors=Grocock CJ, Rebours V, Delhaye MN, Andrén-Sandberg A, Weiss FU, Mountford R, Harcus MJ, Niemczyck E, Vitone LJ, Dodd S, Jørgensen MT, Ammann RW, Schaffalitzky de Muckadell O, Butler JV, Burgess P, Kerr B, Charnley R, Sutton R, Raraty MG, Devière J, Whitcomb DC, Neoptolemos JP, Lévy P, Lerch MM, Greenhalf W |title=The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families |journal=Gut |volume=59 |issue=3 |pages=357–63 |year=2010 |pmid=19951905 |doi=10.1136/gut.2009.186817 |url=}}</ref>
* New mutations at different sites on [[PRSS16|PRSS1]] gene may include:<ref name="pmid10381903">{{cite journal |vauthors=Witt H, Luck W, Becker M |title=A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis |journal=Gastroenterology |volume=117 |issue=1 |pages=7–10 |year=1999 |pmid=10381903 |doi= |url=}}</ref><ref name="pmid19191323">{{cite journal |vauthors=Kereszturi E, Szmola R, Kukor Z, Simon P, Weiss FU, Lerch MM, Sahin-Tóth M |title=Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism |journal=Hum. Mutat. |volume=30 |issue=4 |pages=575–82 |year=2009 |pmid=19191323 |pmc=2663013 |doi=10.1002/humu.20853 |url=}}</ref><ref name="pmid10514442">{{cite journal |vauthors=Sahin-Tóth M |title=Hereditary pancreatitis-associated mutation asn(21) --> ile stabilizes rat trypsinogen in vitro |journal=J. Biol. Chem. |volume=274 |issue=42 |pages=29699–704 |year=1999 |pmid=10514442 |doi= |url=}}</ref><ref name="pmid10930381">{{cite journal |vauthors=Teich N, Ockenga J, Hoffmeister A, Manns M, Mössner J, Keim V |title=Chronic pancreatitis associated with an activation peptide mutation that facilitates trypsin activation |journal=Gastroenterology |volume=119 |issue=2 |pages=461–5 |year=2000 |pmid=10930381 |doi= |url=}}</ref><ref name="pmid11866271">{{cite journal |vauthors=Teich N, Bauer N, Mössner J, Keim V |title=Mutational screening of patients with nonalcoholic chronic pancreatitis: identification of further trypsinogen variants |journal=Am. J. Gastroenterol. |volume=97 |issue=2 |pages=341–6 |year=2002 |pmid=11866271 |doi=10.1111/j.1572-0241.2002.05467.x |url=}}</ref><ref name="pmid19951905">{{cite journal |vauthors=Grocock CJ, Rebours V, Delhaye MN, Andrén-Sandberg A, Weiss FU, Mountford R, Harcus MJ, Niemczyck E, Vitone LJ, Dodd S, Jørgensen MT, Ammann RW, Schaffalitzky de Muckadell O, Butler JV, Burgess P, Kerr B, Charnley R, Sutton R, Raraty MG, Devière J, Whitcomb DC, Neoptolemos JP, Lévy P, Lerch MM, Greenhalf W |title=The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families |journal=Gut |volume=59 |issue=3 |pages=357–63 |year=2010 |pmid=19951905 |doi=10.1136/gut.2009.186817 |url=}}</ref>
** Misfolding and intracellular retention of cationic trypsinogen  
** Misfolding and intracellular retention of [[cationic]] [[trypsinogen]]
** Stabilization of trypsinogen, protecting against autocatalytic degradation
** Stabilization of [[trypsinogen]], protecting against [[autocatalytic]] degradation
** Increases trypsin activation from trypsinogen
** Increases [[trypsin]] activation from [[trypsinogen]]


* Mutations in PRSS1 gene result in  
* Mutations in [[PRSS16|PRSS1]] gene result in  
** Premature activation of digestive enzymes resulting in:
** Premature activation of digestive enzymes resulting in:
*** Pancreatic injury
*** Pancreatic injury
*** Immune system activation
*** [[Immune system]] activation
*** Acute pancreatitis
*** [[Acute pancreatitis]]
*** Chronic pancreatitis
*** [[Chronic pancreatitis]]


===Mode of inheritance:===
===Mode of inheritance:===
Line 49: Line 50:
!Genes involved
!Genes involved
|-
|-
|Autosomal dominant 
|[[Autosomal dominant]] 
|Serine protease 1 gene (''PRSS1'')
|Serine protease 1 gene (''[[PRSS16|PRSS1]]'')
|-
|-
|Autosomal recessive
|[[Autosomal recessive]]
|Serine protease inhibitor Kazal type 1 gene (''SPINK1'', also called pancreatic secretory trypsin inhibitor gene)
|Serine protease inhibitor Kazal type 1 gene (''[[SPINK1]]'', also called pancreatic secretory trypsin inhibitor gene)
|-
|-
|Complex genetics
|Complex genetics
Line 63: Line 64:


===== Mutations in PRSS1 gene: =====
===== Mutations in PRSS1 gene: =====
* Serine protease 1 gene (''PRSS1'') encodes for trypsin-1 (cationic trypsinogen).
* Serine protease 1 gene (''[[PRSS16|PRSS1]]'') encodes for trypsin-1 (cationic trypsinogen).
* 80% of patients with autosomal dominant hereditary pancreatitis have mutations in PRSS1 gene.<ref name="pmid18755888">{{cite journal |vauthors=Rebours V, Boutron-Ruault MC, Schnee M, Férec C, Le Maréchal C, Hentic O, Maire F, Hammel P, Ruszniewski P, Lévy P |title=The natural history of hereditary pancreatitis: a national series |journal=Gut |volume=58 |issue=1 |pages=97–103 |year=2009 |pmid=18755888 |doi=10.1136/gut.2008.149179 |url=}}</ref><ref name="pmid16093768">{{cite journal |vauthors=DiMagno MJ, DiMagno EP |title=Chronic pancreatitis |journal=Curr. Opin. Gastroenterol. |volume=21 |issue=5 |pages=544–54 |year=2005 |pmid=16093768 |doi= |url=}}</ref><ref name="pmid12120221">{{cite journal |vauthors=Applebaum-Shapiro SE, Finch R, Pfützer RH, Hepp LA, Gates L, Amann S, Martin S, Ulrich CD, Whitcomb DC |title=Hereditary pancreatitis in North America: the Pittsburgh-Midwest Multi-Center Pancreatic Study Group Study |journal=Pancreatology |volume=1 |issue=5 |pages=439–43 |year=2001 |pmid=12120221 |doi= |url=}}</ref><ref name="pmid15528017">{{cite journal |vauthors=Howes N, Greenhalf W, Stocken DD, Neoptolemos JP |title=Cationic trypsinogen mutations and pancreatitis |journal=Gastroenterol. Clin. North Am. |volume=33 |issue=4 |pages=767–87 |year=2004 |pmid=15528017 |doi=10.1016/j.gtc.2004.07.003 |url=}}</ref><ref name="pmid15479696">{{cite journal |vauthors=Whitcomb DC |title=Value of genetic testing in the management of pancreatitis |journal=Gut |volume=53 |issue=11 |pages=1710–7 |year=2004 |pmid=15479696 |pmc=1774302 |doi=10.1136/gut.2003.015511 |url=}}</ref><ref name="pmid25556020">{{cite journal |vauthors=Schwarzenberg SJ, Bellin M, Husain SZ, Ahuja M, Barth B, Davis H, Durie PR, Fishman DS, Freedman SD, Gariepy CE, Giefer MJ, Gonska T, Heyman MB, Himes R, Kumar S, Morinville VD, Lowe ME, Nuehring NE, Ooi CY, Pohl JF, Troendle D, Werlin SL, Wilschanski M, Yen E, Uc A |title=Pediatric chronic pancreatitis is associated with genetic risk factors and substantial disease burden |journal=J. Pediatr. |volume=166 |issue=4 |pages=890–896.e1 |year=2015 |pmid=25556020 |pmc=4380827 |doi=10.1016/j.jpeds.2014.11.019 |url=}}</ref>
* 80% of patients with [[autosomal dominant]] hereditary pancreatitis have mutations in [[PRSS16|PRSS1]] gene.<ref name="pmid18755888">{{cite journal |vauthors=Rebours V, Boutron-Ruault MC, Schnee M, Férec C, Le Maréchal C, Hentic O, Maire F, Hammel P, Ruszniewski P, Lévy P |title=The natural history of hereditary pancreatitis: a national series |journal=Gut |volume=58 |issue=1 |pages=97–103 |year=2009 |pmid=18755888 |doi=10.1136/gut.2008.149179 |url=}}</ref><ref name="pmid16093768">{{cite journal |vauthors=DiMagno MJ, DiMagno EP |title=Chronic pancreatitis |journal=Curr. Opin. Gastroenterol. |volume=21 |issue=5 |pages=544–54 |year=2005 |pmid=16093768 |doi= |url=}}</ref><ref name="pmid12120221">{{cite journal |vauthors=Applebaum-Shapiro SE, Finch R, Pfützer RH, Hepp LA, Gates L, Amann S, Martin S, Ulrich CD, Whitcomb DC |title=Hereditary pancreatitis in North America: the Pittsburgh-Midwest Multi-Center Pancreatic Study Group Study |journal=Pancreatology |volume=1 |issue=5 |pages=439–43 |year=2001 |pmid=12120221 |doi= |url=}}</ref><ref name="pmid15528017">{{cite journal |vauthors=Howes N, Greenhalf W, Stocken DD, Neoptolemos JP |title=Cationic trypsinogen mutations and pancreatitis |journal=Gastroenterol. Clin. North Am. |volume=33 |issue=4 |pages=767–87 |year=2004 |pmid=15528017 |doi=10.1016/j.gtc.2004.07.003 |url=}}</ref><ref name="pmid15479696">{{cite journal |vauthors=Whitcomb DC |title=Value of genetic testing in the management of pancreatitis |journal=Gut |volume=53 |issue=11 |pages=1710–7 |year=2004 |pmid=15479696 |pmc=1774302 |doi=10.1136/gut.2003.015511 |url=}}</ref><ref name="pmid25556020">{{cite journal |vauthors=Schwarzenberg SJ, Bellin M, Husain SZ, Ahuja M, Barth B, Davis H, Durie PR, Fishman DS, Freedman SD, Gariepy CE, Giefer MJ, Gonska T, Heyman MB, Himes R, Kumar S, Morinville VD, Lowe ME, Nuehring NE, Ooi CY, Pohl JF, Troendle D, Werlin SL, Wilschanski M, Yen E, Uc A |title=Pediatric chronic pancreatitis is associated with genetic risk factors and substantial disease burden |journal=J. Pediatr. |volume=166 |issue=4 |pages=890–896.e1 |year=2015 |pmid=25556020 |pmc=4380827 |doi=10.1016/j.jpeds.2014.11.019 |url=}}</ref>
* The most common mutations in PRSS1 include R122H and N29I.<ref name="pmid8841182">{{cite journal |vauthors=Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK, Amann ST, Toskes PP, Liddle R, McGrath K, Uomo G, Post JC, Ehrlich GD |title=Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene |journal=Nat. Genet. |volume=14 |issue=2 |pages=141–5 |year=1996 |pmid=8841182 |doi=10.1038/ng1096-141 |url=}}</ref><ref name="pmid9322498">{{cite journal |vauthors=Gorry MC, Gabbaizedeh D, Furey W, Gates LK, Preston RA, Aston CE, Zhang Y, Ulrich C, Ehrlich GD, Whitcomb DC |title=Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis |journal=Gastroenterology |volume=113 |issue=4 |pages=1063–8 |year=1997 |pmid=9322498 |doi= |url=}}</ref><ref name="pmid18755888">{{cite journal |vauthors=Rebours V, Boutron-Ruault MC, Schnee M, Férec C, Le Maréchal C, Hentic O, Maire F, Hammel P, Ruszniewski P, Lévy P |title=The natural history of hereditary pancreatitis: a national series |journal=Gut |volume=58 |issue=1 |pages=97–103 |year=2009 |pmid=18755888 |doi=10.1136/gut.2008.149179 |url=}}</ref><ref name="pmid15479696">{{cite journal |vauthors=Whitcomb DC |title=Value of genetic testing in the management of pancreatitis |journal=Gut |volume=53 |issue=11 |pages=1710–7 |year=2004 |pmid=15479696 |pmc=1774302 |doi=10.1136/gut.2003.015511 |url=}}</ref>
* The most common mutations in [[PRSS16|PRSS1]] include R122H and N29I.<ref name="pmid8841182">{{cite journal |vauthors=Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK, Amann ST, Toskes PP, Liddle R, McGrath K, Uomo G, Post JC, Ehrlich GD |title=Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene |journal=Nat. Genet. |volume=14 |issue=2 |pages=141–5 |year=1996 |pmid=8841182 |doi=10.1038/ng1096-141 |url=}}</ref><ref name="pmid9322498">{{cite journal |vauthors=Gorry MC, Gabbaizedeh D, Furey W, Gates LK, Preston RA, Aston CE, Zhang Y, Ulrich C, Ehrlich GD, Whitcomb DC |title=Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis |journal=Gastroenterology |volume=113 |issue=4 |pages=1063–8 |year=1997 |pmid=9322498 |doi= |url=}}</ref><ref name="pmid18755888">{{cite journal |vauthors=Rebours V, Boutron-Ruault MC, Schnee M, Férec C, Le Maréchal C, Hentic O, Maire F, Hammel P, Ruszniewski P, Lévy P |title=The natural history of hereditary pancreatitis: a national series |journal=Gut |volume=58 |issue=1 |pages=97–103 |year=2009 |pmid=18755888 |doi=10.1136/gut.2008.149179 |url=}}</ref><ref name="pmid15479696">{{cite journal |vauthors=Whitcomb DC |title=Value of genetic testing in the management of pancreatitis |journal=Gut |volume=53 |issue=11 |pages=1710–7 |year=2004 |pmid=15479696 |pmc=1774302 |doi=10.1136/gut.2003.015511 |url=}}</ref>


===== Mutations in SPINK1 gene: =====
===== Mutations in SPINK1 gene: =====
*The serine protease inhibitor Kazal type 1 gene (''SPINK1'') encodes a pancreatic secretory trypsin inhibitor, that is an acute phase reactant protein, suggesting ongoing inflammation.<ref name="pmid16093768">{{cite journal |vauthors=DiMagno MJ, DiMagno EP |title=Chronic pancreatitis |journal=Curr. Opin. Gastroenterol. |volume=21 |issue=5 |pages=544–54 |year=2005 |pmid=16093768 |doi= |url=}}</ref><ref name="pmid17533082">{{cite journal |vauthors=Fink EN, Kant JA, Whitcomb DC |title=Genetic counseling for nonsyndromic pancreatitis |journal=Gastroenterol. Clin. North Am. |volume=36 |issue=2 |pages=325–33, ix |year=2007 |pmid=17533082 |doi=10.1016/j.gtc.2007.03.007 |url=}}</ref><ref name="pmid10982753">{{cite journal |vauthors=Pfützer RH, Barmada MM, Brunskill AP, Finch R, Hart PS, Neoptolemos J, Furey WF, Whitcomb DC |title=SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis |journal=Gastroenterology |volume=119 |issue=3 |pages=615–23 |year=2000 |pmid=10982753 |doi= |url=}}</ref><ref name="pmid11866271">{{cite journal |vauthors=Teich N, Bauer N, Mössner J, Keim V |title=Mutational screening of patients with nonalcoholic chronic pancreatitis: identification of further trypsinogen variants |journal=Am. J. Gastroenterol. |volume=97 |issue=2 |pages=341–6 |year=2002 |pmid=11866271 |doi=10.1111/j.1572-0241.2002.05467.x |url=}}</ref><ref name="pmid10835640">{{cite journal |vauthors=Witt H, Luck W, Hennies HC, Classen M, Kage A, Lass U, Landt O, Becker M |title=Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis |journal=Nat. Genet. |volume=25 |issue=2 |pages=213–6 |year=2000 |pmid=10835640 |doi=10.1038/76088 |url=}}</ref><ref name="pmid15513391">{{cite journal |vauthors=Schneider A, Barmada MM, Slivka A, Martin JA, Whitcomb DC |title=Clinical characterization of patients with idiopathic chronic pancreatitis and SPINK1 Mutations |journal=Scand. J. Gastroenterol. |volume=39 |issue=9 |pages=903–4 |year=2004 |pmid=15513391 |doi=10.1080/00365520410006710 |url=}}</ref>
*The [[serine protease inhibitor]] Kazal type 1 gene (''[[SPINK1]]'') encodes a pancreatic secretory [[trypsin]] inhibitor, that is an acute phase reactant protein, suggesting ongoing [[inflammation]].<ref name="pmid16093768">{{cite journal |vauthors=DiMagno MJ, DiMagno EP |title=Chronic pancreatitis |journal=Curr. Opin. Gastroenterol. |volume=21 |issue=5 |pages=544–54 |year=2005 |pmid=16093768 |doi= |url=}}</ref><ref name="pmid17533082">{{cite journal |vauthors=Fink EN, Kant JA, Whitcomb DC |title=Genetic counseling for nonsyndromic pancreatitis |journal=Gastroenterol. Clin. North Am. |volume=36 |issue=2 |pages=325–33, ix |year=2007 |pmid=17533082 |doi=10.1016/j.gtc.2007.03.007 |url=}}</ref><ref name="pmid10982753">{{cite journal |vauthors=Pfützer RH, Barmada MM, Brunskill AP, Finch R, Hart PS, Neoptolemos J, Furey WF, Whitcomb DC |title=SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis |journal=Gastroenterology |volume=119 |issue=3 |pages=615–23 |year=2000 |pmid=10982753 |doi= |url=}}</ref><ref name="pmid11866271">{{cite journal |vauthors=Teich N, Bauer N, Mössner J, Keim V |title=Mutational screening of patients with nonalcoholic chronic pancreatitis: identification of further trypsinogen variants |journal=Am. J. Gastroenterol. |volume=97 |issue=2 |pages=341–6 |year=2002 |pmid=11866271 |doi=10.1111/j.1572-0241.2002.05467.x |url=}}</ref><ref name="pmid10835640">{{cite journal |vauthors=Witt H, Luck W, Hennies HC, Classen M, Kage A, Lass U, Landt O, Becker M |title=Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis |journal=Nat. Genet. |volume=25 |issue=2 |pages=213–6 |year=2000 |pmid=10835640 |doi=10.1038/76088 |url=}}</ref><ref name="pmid15513391">{{cite journal |vauthors=Schneider A, Barmada MM, Slivka A, Martin JA, Whitcomb DC |title=Clinical characterization of patients with idiopathic chronic pancreatitis and SPINK1 Mutations |journal=Scand. J. Gastroenterol. |volume=39 |issue=9 |pages=903–4 |year=2004 |pmid=15513391 |doi=10.1080/00365520410006710 |url=}}</ref>
*Mutations in SPINK1 may increase the risk of developing chronic pancreatitis by 12 fold when compared to general population.
*Mutations in [[SPINK1]] may increase the risk of developing [[chronic pancreatitis]] by 12 fold when compared to general population.
*CFTR is the most common genetic variant seen with SPINK1.<ref name="pmid20977904">{{cite journal |vauthors=Schneider A, Larusch J, Sun X, Aloe A, Lamb J, Hawes R, Cotton P, Brand RE, Anderson MA, Money ME, Banks PA, Lewis MD, Baillie J, Sherman S, Disario J, Burton FR, Gardner TB, Amann ST, Gelrud A, George R, Rockacy MJ, Kassabian S, Martinson J, Slivka A, Yadav D, Oruc N, Barmada MM, Frizzell R, Whitcomb DC |title=Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis |journal=Gastroenterology |volume=140 |issue=1 |pages=162–71 |year=2011 |pmid=20977904 |pmc=3171690 |doi=10.1053/j.gastro.2010.10.045 |url=}}</ref><ref name="pmid22427236">{{cite journal |vauthors=Rosendahl J, Landt O, Bernadova J, Kovacs P, Teich N, Bödeker H, Keim V, Ruffert C, Mössner J, Kage A, Stumvoll M, Groneberg D, Krüger R, Luck W, Treiber M, Becker M, Witt H |title=CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? |journal=Gut |volume=62 |issue=4 |pages=582–92 |year=2013 |pmid=22427236 |doi=10.1136/gutjnl-2011-300645 |url=}}</ref>
*[[CFTR (gene)|CFTR]] is the most common genetic variant seen with [[SPINK1]].<ref name="pmid20977904">{{cite journal |vauthors=Schneider A, Larusch J, Sun X, Aloe A, Lamb J, Hawes R, Cotton P, Brand RE, Anderson MA, Money ME, Banks PA, Lewis MD, Baillie J, Sherman S, Disario J, Burton FR, Gardner TB, Amann ST, Gelrud A, George R, Rockacy MJ, Kassabian S, Martinson J, Slivka A, Yadav D, Oruc N, Barmada MM, Frizzell R, Whitcomb DC |title=Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis |journal=Gastroenterology |volume=140 |issue=1 |pages=162–71 |year=2011 |pmid=20977904 |pmc=3171690 |doi=10.1053/j.gastro.2010.10.045 |url=}}</ref><ref name="pmid22427236">{{cite journal |vauthors=Rosendahl J, Landt O, Bernadova J, Kovacs P, Teich N, Bödeker H, Keim V, Ruffert C, Mössner J, Kage A, Stumvoll M, Groneberg D, Krüger R, Luck W, Treiber M, Becker M, Witt H |title=CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? |journal=Gut |volume=62 |issue=4 |pages=582–92 |year=2013 |pmid=22427236 |doi=10.1136/gutjnl-2011-300645 |url=}}</ref>
* SPINK variants are also found to be associated with:
* [[SPINK1|SPINK]] variants are also found to be associated with:<ref name="pmid18414673">{{cite journal |vauthors=Aoun E, Chang CC, Greer JB, Papachristou GI, Barmada MM, Whitcomb DC |title=Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis |journal=PLoS ONE |volume=3 |issue=4 |pages=e2003 |year=2008 |pmid=18414673 |pmc=2289874 |doi=10.1371/journal.pone.0002003 |url=}}</ref>
** Idiopathic pancreatitis
** Idiopathic pancreatitis
** Alcoholic pancreatitis
** Alcoholic pancreatitis
Line 78: Line 79:


===== Mutations in CFTR  gene: =====
===== Mutations in CFTR  gene: =====
* [[CFTR gene|CFTR]] gene mutations may cause pancreatitis with or without [[cystic]] [[fibrosis]].<ref name="pmid12940920">{{cite journal |vauthors=Rowntree RK, Harris A |title=The phenotypic consequences of CFTR mutations |journal=Ann. Hum. Genet. |volume=67 |issue=Pt 5 |pages=471–85 |year=2003 |pmid=12940920 |doi= |url=}}</ref><ref name="pmid9725922">{{cite journal |vauthors=Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS |title=Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis |journal=N. Engl. J. Med. |volume=339 |issue=10 |pages=653–8 |year=1998 |pmid=9725922 |doi=10.1056/NEJM199809033391002 |url=}}</ref><ref name="pmid20923678">{{cite journal |vauthors=Ooi CY, Dorfman R, Cipolli M, Gonska T, Castellani C, Keenan K, Freedman SD, Zielenski J, Berthiaume Y, Corey M, Schibli S, Tullis E, Durie PR |title=Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis |journal=Gastroenterology |volume=140 |issue=1 |pages=153–61 |year=2011 |pmid=20923678 |doi=10.1053/j.gastro.2010.09.046 |url=}}</ref><ref name="pmid15749233">{{cite journal |vauthors=Cohn JA, Mitchell RM, Jowell PS |title=The impact of cystic fibrosis and PSTI/SPINK1 gene mutations on susceptibility to chronic pancreatitis |journal=Clin. Lab. Med. |volume=25 |issue=1 |pages=79–100 |year=2005 |pmid=15749233 |doi=10.1016/j.cll.2004.12.007 |url=}}</ref><ref name="pmid20977904">{{cite journal |vauthors=Schneider A, Larusch J, Sun X, Aloe A, Lamb J, Hawes R, Cotton P, Brand RE, Anderson MA, Money ME, Banks PA, Lewis MD, Baillie J, Sherman S, Disario J, Burton FR, Gardner TB, Amann ST, Gelrud A, George R, Rockacy MJ, Kassabian S, Martinson J, Slivka A, Yadav D, Oruc N, Barmada MM, Frizzell R, Whitcomb DC |title=Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis |journal=Gastroenterology |volume=140 |issue=1 |pages=162–71 |year=2011 |pmid=20977904 |pmc=3171690 |doi=10.1053/j.gastro.2010.10.045 |url=}}</ref><ref name="pmid21844754">{{cite journal |vauthors=LaRusch J, Whitcomb DC |title=Genetics of pancreatitis |journal=Curr. Opin. Gastroenterol. |volume=27 |issue=5 |pages=467–74 |year=2011 |pmid=21844754 |pmc=3704192 |doi=10.1097/MOG.0b013e328349e2f8 |url=}}</ref>
<ref name="pmid15987793">{{cite journal |vauthors=Weiss FU, Simon P, Bogdanova N, Mayerle J, Dworniczak B, Horst J, Lerch MM |title=Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls |journal=Gut |volume=54 |issue=10 |pages=1456–60 |year=2005 |pmid=15987793 |pmc=1774703 |doi=10.1136/gut.2005.064808 |url=}}</ref><ref name="pmid16134171">{{cite journal |vauthors=Cohn JA, Neoptolemos JP, Feng J, Yan J, Jiang Z, Greenhalf W, McFaul C, Mountford R, Sommer SS |title=Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers |journal=Hum. Mutat. |volume=26 |issue=4 |pages=303–7 |year=2005 |pmid=16134171 |doi=10.1002/humu.20232 |url=}}</ref><ref name="pmid22158025">{{cite journal |vauthors=Bertin C, Pelletier AL, Vullierme MP, Bienvenu T, Rebours V, Hentic O, Maire F, Hammel P, Vilgrain V, Ruszniewski P, Lévy P |title=Pancreas divisum is not a cause of pancreatitis by itself but acts as a partner of genetic mutations |journal=Am. J. Gastroenterol. |volume=107 |issue=2 |pages=311–7 |year=2012 |pmid=22158025 |doi=10.1038/ajg.2011.424 |url=}}</ref><ref name="pmid15307877">{{cite journal |vauthors=Gelrud A, Sheth S, Banerjee S, Weed D, Shea J, Chuttani R, Howell DA, Telford JJ, Carr-Locke DL, Regan MM, Ellis L, Durie PR, Freedman SD |title=Analysis of cystic fibrosis gener product (CFTR) function in patients with pancreas divisum and recurrent acute pancreatitis |journal=Am. J. Gastroenterol. |volume=99 |issue=8 |pages=1557–62 |year=2004 |pmid=15307877 |doi=10.1111/j.1572-0241.2004.30834.x |url=}}</ref>


===== Mutations in CTRC gene: =====
===== Mutations in CTRC gene: =====
* The chymotrypsin C gene (''[https://en.wikipedia.org/wiki/Chymotrypsin-C CTRC]'') encodes for Chymotrypsin C, that is a digestive enzyme, that helps in [[trypsin]] degradation.
* Mutations in [https://en.wikipedia.org/wiki/Chymotrypsin-C CTRC] gene are found to be associated with chronic hereditary pancreatitis.<ref name="pmid22427236">{{cite journal |vauthors=Rosendahl J, Landt O, Bernadova J, Kovacs P, Teich N, Bödeker H, Keim V, Ruffert C, Mössner J, Kage A, Stumvoll M, Groneberg D, Krüger R, Luck W, Treiber M, Becker M, Witt H |title=CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? |journal=Gut |volume=62 |issue=4 |pages=582–92 |year=2013 |pmid=22427236 |doi=10.1136/gutjnl-2011-300645 |url=}}</ref><ref name="pmid18059268">{{cite journal |vauthors=Rosendahl J, Witt H, Szmola R, Bhatia E, Ozsvári B, Landt O, Schulz HU, Gress TM, Pfützer R, Löhr M, Kovacs P, Blüher M, Stumvoll M, Choudhuri G, Hegyi P, te Morsche RH, Drenth JP, Truninger K, Macek M, Puhl G, Witt U, Schmidt H, Büning C, Ockenga J, Kage A, Groneberg DA, Nickel R, Berg T, Wiedenmann B, Bödeker H, Keim V, Mössner J, Teich N, Sahin-Tóth M |title=Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis |journal=Nat. Genet. |volume=40 |issue=1 |pages=78–82 |year=2008 |pmid=18059268 |pmc=2650829 |doi=10.1038/ng.2007.44 |url=}}</ref><ref name="pmid18172691">{{cite journal |vauthors=Masson E, Chen JM, Scotet V, Le Maréchal C, Férec C |title=Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis |journal=Hum. Genet. |volume=123 |issue=1 |pages=83–91 |year=2008 |pmid=18172691 |doi=10.1007/s00439-007-0459-3 |url=}}</ref><ref name="pmid25569187">{{cite journal |vauthors=LaRusch J, Lozano-Leon A, Stello K, Moore A, Muddana V, O'Connell M, Diergaarde B, Yadav D, Whitcomb DC |title=The Common Chymotrypsinogen C (CTRC) Variant G60G (C.180T) Increases Risk of Chronic Pancreatitis But Not Recurrent Acute Pancreatitis in a North American Population |journal=Clin Transl Gastroenterol |volume=6 |issue= |pages=e68 |year=2015 |pmid=25569187 |pmc=4418406 |doi=10.1038/ctg.2014.13 |url=}}</ref><ref name="pmid22942235">{{cite journal |vauthors=Beer S, Zhou J, Szabó A, Keiles S, Chandak GR, Witt H, Sahin-Tóth M |title=Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk |journal=Gut |volume=62 |issue=11 |pages=1616–24 |year=2013 |pmid=22942235 |pmc=3660471 |doi=10.1136/gutjnl-2012-303090 |url=}}</ref>


===== Mutations in other genes: =====
===== Mutations in other genes: =====
* Two additional genes have been found to be associated with hereditary pancreatitis.
** [[CLDN2]], associated with chronic alcoholic pancreatitis.<ref name="pmid23622139">{{cite journal |vauthors=Whitcomb DC |title=Genetic risk factors for pancreatic disorders |journal=Gastroenterology |volume=144 |issue=6 |pages=1292–302 |year=2013 |pmid=23622139 |pmc=3684061 |doi=10.1053/j.gastro.2013.01.069 |url=}}</ref><ref name="pmid25253127">{{cite journal |vauthors=Derikx MH, Kovacs P, Scholz M, Masson E, Chen JM, Ruffert C, Lichtner P, Te Morsche RH, Cavestro GM, Férec C, Drenth JP, Witt H, Rosendahl J |title=Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study |journal=Gut |volume=64 |issue=9 |pages=1426–33 |year=2015 |pmid=25253127 |doi=10.1136/gutjnl-2014-307453 |url=}}</ref><ref name="pmid26002935">{{cite journal |vauthors=Masamune A, Nakano E, Hamada S, Kakuta Y, Kume K, Shimosegawa T |title=Common variants at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with chronic pancreatitis in Japan |journal=Gut |volume=64 |issue=8 |pages=1345–6 |year=2015 |pmid=26002935 |doi=10.1136/gutjnl-2015-309802 |url=}}</ref>
** [https://en.wikipedia.org/wiki/Carboxypeptidase_A1 CPA1], associated with nonalcoholic chronic pancreatitis, especially with early age of onset.<ref name="pmid23955596">{{cite journal |vauthors=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 |title=Variants in CPA1 are strongly associated with early onset chronic pancreatitis |journal=Nat. Genet. |volume=45 |issue=10 |pages=1216–20 |year=2013 |pmid=23955596 |pmc=3909499 |doi=10.1038/ng.2730 |url=}}</ref>


===== Common mutations: =====
===== Common mutations: =====
* The most common disease associated mutations in PRSS1 gene include:<ref name="pmid8841182">{{cite journal |vauthors=Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK, Amann ST, Toskes PP, Liddle R, McGrath K, Uomo G, Post JC, Ehrlich GD |title=Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene |journal=Nat. Genet. |volume=14 |issue=2 |pages=141–5 |year=1996 |pmid=8841182 |doi=10.1038/ng1096-141 |url=}}</ref><ref name="pmid9322498">{{cite journal |vauthors=Gorry MC, Gabbaizedeh D, Furey W, Gates LK, Preston RA, Aston CE, Zhang Y, Ulrich C, Ehrlich GD, Whitcomb DC |title=Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis |journal=Gastroenterology |volume=113 |issue=4 |pages=1063–8 |year=1997 |pmid=9322498 |doi= |url=}}</ref><ref name="pmid9633818">{{cite journal |vauthors=Teich N, Mössner J, Keim V |title=Mutations of the cationic trypsinogen in hereditary pancreatitis |journal=Hum. Mutat. |volume=12 |issue=1 |pages=39–43 |year=1998 |pmid=9633818 |doi=10.1002/(SICI)1098-1004(1998)12:1<39::AID-HUMU6>3.0.CO;2-P |url=}}</ref>
* The most common disease associated mutations in [[PRSS16|PRSS1]] gene include:<ref name="pmid8841182">{{cite journal |vauthors=Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK, Amann ST, Toskes PP, Liddle R, McGrath K, Uomo G, Post JC, Ehrlich GD |title=Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene |journal=Nat. Genet. |volume=14 |issue=2 |pages=141–5 |year=1996 |pmid=8841182 |doi=10.1038/ng1096-141 |url=}}</ref><ref name="pmid9322498">{{cite journal |vauthors=Gorry MC, Gabbaizedeh D, Furey W, Gates LK, Preston RA, Aston CE, Zhang Y, Ulrich C, Ehrlich GD, Whitcomb DC |title=Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis |journal=Gastroenterology |volume=113 |issue=4 |pages=1063–8 |year=1997 |pmid=9322498 |doi= |url=}}</ref><ref name="pmid9633818">{{cite journal |vauthors=Teich N, Mössner J, Keim V |title=Mutations of the cationic trypsinogen in hereditary pancreatitis |journal=Hum. Mutat. |volume=12 |issue=1 |pages=39–43 |year=1998 |pmid=9633818 |doi=10.1002/(SICI)1098-1004(1998)12:1<39::AID-HUMU6>3.0.CO;2-P |url=}}</ref>
** R122H<ref name="pmid8841182">{{cite journal |vauthors=Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK, Amann ST, Toskes PP, Liddle R, McGrath K, Uomo G, Post JC, Ehrlich GD |title=Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene |journal=Nat. Genet. |volume=14 |issue=2 |pages=141–5 |year=1996 |pmid=8841182 |doi=10.1038/ng1096-141 |url=}}</ref>
** R122H<ref name="pmid8841182">{{cite journal |vauthors=Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK, Amann ST, Toskes PP, Liddle R, McGrath K, Uomo G, Post JC, Ehrlich GD |title=Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene |journal=Nat. Genet. |volume=14 |issue=2 |pages=141–5 |year=1996 |pmid=8841182 |doi=10.1038/ng1096-141 |url=}}</ref>
** N29I 
** N29I 
** A16V
** A16V
* Other genes may include:
 
** PRSS2, the anionic trypsinogen gene
===== Protective genetic variants: =====
* There are 2 genetic variants that have been found to play an important role in protecting against pancreatitis. They include:
** PRSS2 G191R mutation<ref name="pmid16699518">{{cite journal |vauthors=Witt H, Sahin-Tóth M, Landt O, Chen JM, Kähne T, Drenth JP, Kukor Z, Szepessy E, Halangk W, Dahm S, Rohde K, Schulz HU, Le Maréchal C, Akar N, Ammann RW, Truninger K, Bargetzi M, Bhatia E, Castellani C, Cavestro GM, Cerny M, Destro-Bisol G, Spedini G, Eiberg H, Jansen JB, Koudova M, Rausova E, Macek M, Malats N, Real FX, Menzel HJ, Moral P, Galavotti R, Pignatti PF, Rickards O, Spicak J, Zarnescu NO, Böck W, Gress TM, Friess H, Ockenga J, Schmidt H, Pfützer R, Löhr M, Simon P, Weiss FU, Lerch MM, Teich N, Keim V, Berg T, Wiedenmann B, Luck W, Groneberg DA, Becker M, Keil T, Kage A, Bernardova J, Braun M, Güldner C, Halangk J, Rosendahl J, Witt U, Treiber M, Nickel R, Férec C |title=A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis |journal=Nat. Genet. |volume=38 |issue=6 |pages=668–73 |year=2006 |pmid=16699518 |pmc=2746914 |doi=10.1038/ng1797 |url=}}</ref><ref name="pmid18362849">{{cite journal |vauthors=Santhosh S, Witt H, te Morsche RH, Nemoda Z, Molnár T, Pap A, Jansen JB, Drenth JP |title=A loss of function polymorphism (G191R) of anionic trypsinogen (PRSS2) confers protection against chronic pancreatitis |journal=Pancreas |volume=36 |issue=3 |pages=317–20 |year=2008 |pmid=18362849 |doi=10.1097/MPA.0b013e31815db4b3 |url=}}</ref>
** ''PRSS1-PRSS2'' locus mutation<ref name="pmid23143602">{{cite journal |vauthors=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 |title=Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis |journal=Nat. Genet. |volume=44 |issue=12 |pages=1349–54 |year=2012 |pmid=23143602 |pmc=3510344 |doi=10.1038/ng.2466 |url=}}</ref><ref name="pmid23622139">{{cite journal |vauthors=Whitcomb DC |title=Genetic risk factors for pancreatic disorders |journal=Gastroenterology |volume=144 |issue=6 |pages=1292–302 |year=2013 |pmid=23622139 |pmc=3684061 |doi=10.1053/j.gastro.2013.01.069 |url=}}</ref>


==Associated Conditions==
==Associated Conditions==
Hereditary pancreatitis may be associated with following syndromes:
Hereditary pancreatitis may be associated with following syndromes:
* Shwachman-Diamond syndrome (SDS) 
* [[Shwachman-Diamond syndrome]] (SDS)<ref name="pmid12496757">{{cite journal |vauthors=Boocock GR, Morrison JA, Popovic M, Richards N, Ellis L, Durie PR, Rommens JM |title=Mutations in SBDS are associated with Shwachman-Diamond syndrome |journal=Nat. Genet. |volume=33 |issue=1 |pages=97–101 |year=2003 |pmid=12496757 |doi=10.1038/ng1062 |url=}}</ref> 
* Pearson marrow pancreas syndrome  
* Pearson marrow pancreas syndrome<ref name="pmid2243133">{{cite journal |vauthors=Rötig A, Cormier V, Blanche S, Bonnefont JP, Ledeist F, Romero N, Schmitz J, Rustin P, Fischer A, Saudubray JM |title=Pearson's marrow-pancreas syndrome. A multisystem mitochondrial disorder in infancy |journal=J. Clin. Invest. |volume=86 |issue=5 |pages=1601–8 |year=1990 |pmid=2243133 |pmc=296909 |doi=10.1172/JCI114881 |url=}}</ref><ref name="pmid2242473">{{cite journal |vauthors=Hopewell JW, Barnes DW, Robbins ME, Corp M, Sansom JM, Young CM, Wiernik G |title=The relative biological effectiveness of fractionated doses of fast neutrons (42 MeVd----Be) for normal tissues in the pig. II. Late effects on cutaneous and subcutaneous tissues |journal=Br J Radiol |volume=63 |issue=754 |pages=760–70 |year=1990 |pmid=2242473 |doi=10.1259/0007-1285-63-754-760 |url=}}</ref> <ref name="pmid10333230">{{cite journal |vauthors=Becher MW, Wills ML, Noll WW, Hurko O, Price DL |title=Kearns-Sayre syndrome with features of Pearson's marrow-pancreas syndrome and a novel 2905-base pair mitochondrial DNA deletion |journal=Hum. Pathol. |volume=30 |issue=5 |pages=577–81 |year=1999 |pmid=10333230 |doi= |url=}}</ref>
* CEL maturity-onset diabetes of the young (''CEL''-MODY)
* CEL maturity-onset diabetes of the young (''CEL''-MODY)<ref name="pmid16369531">{{cite journal |vauthors=Raeder H, Johansson S, Holm PI, Haldorsen IS, Mas E, Sbarra V, Nermoen I, Eide SA, Grevle L, Bjørkhaug L, Sagen JV, Aksnes L, Søvik O, Lombardo D, Molven A, Njølstad PR |title=Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction |journal=Nat. Genet. |volume=38 |issue=1 |pages=54–62 |year=2006 |pmid=16369531 |doi=10.1038/ng1708 |url=}}</ref>
* Johanson-Blizzard syndrome
* [[Johanson-Blizzard syndrome]]<ref name="pmid16311597">{{cite journal |vauthors=Zenker M, Mayerle J, Lerch MM, Tagariello A, Zerres K, Durie PR, Beier M, Hülskamp G, Guzman C, Rehder H, Beemer FA, Hamel B, Vanlieferinghen P, Gershoni-Baruch R, Vieira MW, Dumic M, Auslender R, Gil-da-Silva-Lopes VL, Steinlicht S, Rauh M, Shalev SA, Thiel C, Ekici AB, Winterpacht A, Kwon YT, Varshavsky A, Reis A |title=Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome) |journal=Nat. Genet. |volume=37 |issue=12 |pages=1345–50 |year=2005 |pmid=16311597 |doi=10.1038/ng1681 |url=}}</ref>


==Gross Pathology==
==Gross Pathology==
*On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
*On gross examination, following findings may be observed:
**Enlarged or [[atrophic]] pancreas
**[[Cysts]]
**[[Calcification|Calcifications]]
**[[Fibrosis]]


==Microscopic Pathology==
==Microscopic Pathology==
*On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
*On microscopic histopathological analysis, non-invasive [[Dysplastic change|dysplastic]] intraductal lesions, called pancreatic intraepithelial neoplasia (PanIN), may be noticed.
*Pancreatic intraepithelial neoplasia (PanIN) lesions, are precursors of infiltrating [[ductal carcinoma]].
* PanINs are thought to progress from low grade [[dysplasia]] to high grade [[dysplasia]].
**Low grade [[dysplasia]] (PanIN-1A and PanIN-1B)
**Moderate dysplasia (PanIN-2)
**High grade dysplasia and or carcinoma ''in situ'' (PanIN-3)
 
* Other findings may include:
** Ductal [[inflammation]]
** [[Fibrosis]]


==References==
==References==

Latest revision as of 18:48, 31 January 2018

Hereditary pancreatitis Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Hereditary pancreatitis from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Criteria

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-ray

Echocardiography and Ultrasound

CT scan

MRI

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Guidelines for Management

Case Studies

Case #1

Hereditary pancreatitis pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Hereditary pancreatitis pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Hereditary pancreatitis pathophysiology

CDC on Hereditary pancreatitis pathophysiology

Hereditary pancreatitis pathophysiology in the news

Blogs on Hereditary pancreatitis pathophysiology

Directions to Hospitals Treating Psoriasis

Risk calculators and risk factors for Hereditary pancreatitis pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2]

Overview

Hereditary pancreatitis is caused by genetic mutations in the regulatory regions present on trypsin. Mutations in PRSS1, SPINK1, CTRC, and CFTR gene result in weakening of defense mechanisms against pancreatitis. Defense mechanisms against pancreatitis include control of trypsin activity via prevention of premature activation of trypsinogen to trypsin and destruction, inhibition, or elimination of trypsin from the pancreas. Premature activation of digestive enzymes resulting in pancreatic injury, immune system activation, acute pancreatitis, and chronic pancreatitis. Hereditary pancreatitis may be associated with Shwachman-Diamond syndrome (SDS), Pearson marrow pancreas syndrome, CEL maturity-onset diabetes of the young (CEL-MODY) and Johanson-Blizzard syndrome. Gross examination may show enlarged or atrophic pancreas, cysts, calcifications and fibrosis. On microscopic histopathological analysis, non-invasive dysplastic intraductal lesions, called pancreatic intraepithelial neoplasia (PanIN), may be noticed.

Pathophysiology

Hereditary pancreatitis is defined as EITHER two or more individuals with pancreatitis in two or more generations of a family (i.e., an autosomal dominant pattern of inheritance) OR Pancreatitis associated with a known germline pathogenic variant.[1]

Pathogenesis:

Regulatory regions of trypsin:

  • There are two regulatory regions present on trypsin
  • Almost all of the genetic mutations associated with hereditary pancreatitis are clustered in these 2 regulatory regions
(a) Regulatory region on the activation site 
  • It regulates the activation site
  • It converts trypsinogen into trypsin
(b) Regulatory region on the autolysis site 
  • It regulates the autolysis site
  •  It causes destruction of trypsin

Abnormal regulation of trypsin:

  • Mutations in PRSS1, SPINK1, CTRC, and CFTR gene result in weakening of defense mechanisms against pancreatitis.[2] [3][4]
  • Defense mechanisms against pancreatitis include control of trypsin activity via:
    • Prevention of premature activation of trypsinogen to trypsin
    • Destruction, inhibition, or elimination of trypsin from the pancreas

Mutations at different sites on PRSS1 gene:

Mode of inheritance:

Mode of inheritance Genes involved
Autosomal dominant  Serine protease 1 gene (PRSS1)
Autosomal recessive Serine protease inhibitor Kazal type 1 gene (SPINK1, also called pancreatic secretory trypsin inhibitor gene)
Complex genetics A combination of genetic and environmental factors

Genetics

Hereditary pancreatitis involves mutations in the following genes:

Mutations in PRSS1 gene:
Mutations in SPINK1 gene:
Mutations in CFTR  gene:

[34][35][36][37]

Mutations in CTRC gene:
  • The chymotrypsin C gene (CTRC) encodes for Chymotrypsin C, that is a digestive enzyme, that helps in trypsin degradation.
  • Mutations in CTRC gene are found to be associated with chronic hereditary pancreatitis.[17][38][39][40][41]
Mutations in other genes:
  • Two additional genes have been found to be associated with hereditary pancreatitis.
    • CLDN2, associated with chronic alcoholic pancreatitis.[42][43][44]
    • CPA1, associated with nonalcoholic chronic pancreatitis, especially with early age of onset.[45]
Common mutations:
Protective genetic variants:
  • There are 2 genetic variants that have been found to play an important role in protecting against pancreatitis. They include:

Associated Conditions

Hereditary pancreatitis may be associated with following syndromes:

Gross Pathology

Microscopic Pathology

  • On microscopic histopathological analysis, non-invasive dysplastic intraductal lesions, called pancreatic intraepithelial neoplasia (PanIN), may be noticed.
  • Pancreatic intraepithelial neoplasia (PanIN) lesions, are precursors of infiltrating ductal carcinoma.
  •  PanINs are thought to progress from low grade dysplasia to high grade dysplasia.
    • Low grade dysplasia (PanIN-1A and PanIN-1B)
    • Moderate dysplasia (PanIN-2)
    • High grade dysplasia and or carcinoma in situ (PanIN-3)

References

  1. ↑ Whitcomb DC, Ulrich CD (1999). "Hereditary pancreatitis: new insights, new directions". Baillieres Best Pract Res Clin Gastroenterol. 13 (2): 253–63. PMID 11030605.
  2. ↑ Whitcomb DC (2010). "Genetic aspects of pancreatitis". Annu. Rev. Med. 61: 413–24. doi:10.1146/annurev.med.041608.121416. PMID 20059346.
  3. ↑ 3.0 3.1 Witt H, Luck W, Becker M (1999). "A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis". Gastroenterology. 117 (1): 7–10. PMID 10381903.
  4. ↑ Creighton J, Lyall R, Wilson DI, Curtis A, Charnley R (1999). "Mutations of the cationic trypsinogen gene in patients with chronic pancreatitis". Lancet. 354 (9172): 42–3. doi:10.1016/S0140-6736(99)01814-0. PMID 10406366.
  5. ↑ Kereszturi E, Szmola R, Kukor Z, Simon P, Weiss FU, Lerch MM, Sahin-Tóth M (2009). "Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism". Hum. Mutat. 30 (4): 575–82. doi:10.1002/humu.20853. PMC 2663013. PMID 19191323.
  6. ↑ Sahin-Tóth M (1999). "Hereditary pancreatitis-associated mutation asn(21) --> ile stabilizes rat trypsinogen in vitro". J. Biol. Chem. 274 (42): 29699–704. PMID 10514442.
  7. ↑ Teich N, Ockenga J, Hoffmeister A, Manns M, Mössner J, Keim V (2000). "Chronic pancreatitis associated with an activation peptide mutation that facilitates trypsin activation". Gastroenterology. 119 (2): 461–5. PMID 10930381.
  8. ↑ 8.0 8.1 Teich N, Bauer N, Mössner J, Keim V (2002). "Mutational screening of patients with nonalcoholic chronic pancreatitis: identification of further trypsinogen variants". Am. J. Gastroenterol. 97 (2): 341–6. doi:10.1111/j.1572-0241.2002.05467.x. PMID 11866271.
  9. ↑ Grocock CJ, Rebours V, Delhaye MN, Andrén-Sandberg A, Weiss FU, Mountford R, Harcus MJ, Niemczyck E, Vitone LJ, Dodd S, Jørgensen MT, Ammann RW, Schaffalitzky de Muckadell O, Butler JV, Burgess P, Kerr B, Charnley R, Sutton R, Raraty MG, Devière J, Whitcomb DC, Neoptolemos JP, Lévy P, Lerch MM, Greenhalf W (2010). "The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families". Gut. 59 (3): 357–63. doi:10.1136/gut.2009.186817. PMID 19951905.
  10. ↑ Whitcomb DC, Preston RA, Aston CE, Sossenheimer MJ, Barua PS, Zhang Y, Wong-Chong A, White GJ, Wood PG, Gates LK, Ulrich C, Martin SP, Post JC, Ehrlich GD (1996). "A gene for hereditary pancreatitis maps to chromosome 7q35". Gastroenterology. 110 (6): 1975–80. PMID 8964426.
  11. ↑ 11.0 11.1 11.2 11.3 Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK, Amann ST, Toskes PP, Liddle R, McGrath K, Uomo G, Post JC, Ehrlich GD (1996). "Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene". Nat. Genet. 14 (2): 141–5. doi:10.1038/ng1096-141. PMID 8841182.
  12. ↑ 12.0 12.1 12.2 Gorry MC, Gabbaizedeh D, Furey W, Gates LK, Preston RA, Aston CE, Zhang Y, Ulrich C, Ehrlich GD, Whitcomb DC (1997). "Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis". Gastroenterology. 113 (4): 1063–8. PMID 9322498.
  13. ↑ Howes N, Lerch MM, Greenhalf W, Stocken DD, Ellis I, Simon P, Truninger K, Ammann R, Cavallini G, Charnley RM, Uomo G, Delhaye M, Spicak J, Drumm B, Jansen J, Mountford R, Whitcomb DC, Neoptolemos JP (2004). "Clinical and genetic characteristics of hereditary pancreatitis in Europe". Clin. Gastroenterol. Hepatol. 2 (3): 252–61. PMID 15017610.
  14. ↑ LaFemina J, Roberts PA, Hung YP, Gusella JF, Sahani D, Fernández-del Castillo C, Warshaw AL, Thayer SP (2009). "Identification of a novel kindred with familial pancreatitis and pancreatic cancer". Pancreatology. 9 (3): 273–9. doi:10.1159/000201553. PMC 3713708. PMID 19407482.
  15. ↑ LaRusch J, Barmada MM, Solomon S, Whitcomb DC (2012). "Whole exome sequencing identifies multiple, complex etiologies in an idiopathic hereditary pancreatitis kindred". JOP. 13 (3): 258–62. PMC 3651649. PMID 22572128.
  16. ↑ 16.0 16.1 16.2 Schneider A, Larusch J, Sun X, Aloe A, Lamb J, Hawes R, Cotton P, Brand RE, Anderson MA, Money ME, Banks PA, Lewis MD, Baillie J, Sherman S, Disario J, Burton FR, Gardner TB, Amann ST, Gelrud A, George R, Rockacy MJ, Kassabian S, Martinson J, Slivka A, Yadav D, Oruc N, Barmada MM, Frizzell R, Whitcomb DC (2011). "Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis". Gastroenterology. 140 (1): 162–71. doi:10.1053/j.gastro.2010.10.045. PMC 3171690. PMID 20977904.
  17. ↑ 17.0 17.1 17.2 Rosendahl J, Landt O, Bernadova J, Kovacs P, Teich N, Bödeker H, Keim V, Ruffert C, Mössner J, Kage A, Stumvoll M, Groneberg D, Krüger R, Luck W, Treiber M, Becker M, Witt H (2013). "CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated?". Gut. 62 (4): 582–92. doi:10.1136/gutjnl-2011-300645. PMID 22427236.
  18. ↑ 18.0 18.1 Rebours V, Boutron-Ruault MC, Schnee M, Férec C, Le Maréchal C, Hentic O, Maire F, Hammel P, Ruszniewski P, Lévy P (2009). "The natural history of hereditary pancreatitis: a national series". Gut. 58 (1): 97–103. doi:10.1136/gut.2008.149179. PMID 18755888.
  19. ↑ 19.0 19.1 DiMagno MJ, DiMagno EP (2005). "Chronic pancreatitis". Curr. Opin. Gastroenterol. 21 (5): 544–54. PMID 16093768.
  20. ↑ Applebaum-Shapiro SE, Finch R, Pfützer RH, Hepp LA, Gates L, Amann S, Martin S, Ulrich CD, Whitcomb DC (2001). "Hereditary pancreatitis in North America: the Pittsburgh-Midwest Multi-Center Pancreatic Study Group Study". Pancreatology. 1 (5): 439–43. PMID 12120221.
  21. ↑ Howes N, Greenhalf W, Stocken DD, Neoptolemos JP (2004). "Cationic trypsinogen mutations and pancreatitis". Gastroenterol. Clin. North Am. 33 (4): 767–87. doi:10.1016/j.gtc.2004.07.003. PMID 15528017.
  22. ↑ 22.0 22.1 Whitcomb DC (2004). "Value of genetic testing in the management of pancreatitis". Gut. 53 (11): 1710–7. doi:10.1136/gut.2003.015511. PMC 1774302. PMID 15479696.
  23. ↑ Schwarzenberg SJ, Bellin M, Husain SZ, Ahuja M, Barth B, Davis H, Durie PR, Fishman DS, Freedman SD, Gariepy CE, Giefer MJ, Gonska T, Heyman MB, Himes R, Kumar S, Morinville VD, Lowe ME, Nuehring NE, Ooi CY, Pohl JF, Troendle D, Werlin SL, Wilschanski M, Yen E, Uc A (2015). "Pediatric chronic pancreatitis is associated with genetic risk factors and substantial disease burden". J. Pediatr. 166 (4): 890–896.e1. doi:10.1016/j.jpeds.2014.11.019. PMC 4380827. PMID 25556020.
  24. ↑ Fink EN, Kant JA, Whitcomb DC (2007). "Genetic counseling for nonsyndromic pancreatitis". Gastroenterol. Clin. North Am. 36 (2): 325–33, ix. doi:10.1016/j.gtc.2007.03.007. PMID 17533082.
  25. ↑ Pfützer RH, Barmada MM, Brunskill AP, Finch R, Hart PS, Neoptolemos J, Furey WF, Whitcomb DC (2000). "SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis". Gastroenterology. 119 (3): 615–23. PMID 10982753.
  26. ↑ 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.
  27. ↑ Schneider A, Barmada MM, Slivka A, Martin JA, Whitcomb DC (2004). "Clinical characterization of patients with idiopathic chronic pancreatitis and SPINK1 Mutations". Scand. J. Gastroenterol. 39 (9): 903–4. doi:10.1080/00365520410006710. PMID 15513391.
  28. ↑ Aoun E, Chang CC, Greer JB, Papachristou GI, Barmada MM, Whitcomb DC (2008). "Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis". PLoS ONE. 3 (4): e2003. doi:10.1371/journal.pone.0002003. PMC 2289874. PMID 18414673.
  29. ↑ Rowntree RK, Harris A (2003). "The phenotypic consequences of CFTR mutations". Ann. Hum. Genet. 67 (Pt 5): 471–85. PMID 12940920.
  30. ↑ Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS (1998). "Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis". N. Engl. J. Med. 339 (10): 653–8. doi:10.1056/NEJM199809033391002. PMID 9725922.
  31. ↑ Ooi CY, Dorfman R, Cipolli M, Gonska T, Castellani C, Keenan K, Freedman SD, Zielenski J, Berthiaume Y, Corey M, Schibli S, Tullis E, Durie PR (2011). "Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis". Gastroenterology. 140 (1): 153–61. doi:10.1053/j.gastro.2010.09.046. PMID 20923678.
  32. ↑ Cohn JA, Mitchell RM, Jowell PS (2005). "The impact of cystic fibrosis and PSTI/SPINK1 gene mutations on susceptibility to chronic pancreatitis". Clin. Lab. Med. 25 (1): 79–100. doi:10.1016/j.cll.2004.12.007. PMID 15749233.
  33. ↑ LaRusch J, Whitcomb DC (2011). "Genetics of pancreatitis". Curr. Opin. Gastroenterol. 27 (5): 467–74. doi:10.1097/MOG.0b013e328349e2f8. PMC 3704192. PMID 21844754.
  34. ↑ Weiss FU, Simon P, Bogdanova N, Mayerle J, Dworniczak B, Horst J, Lerch MM (2005). "Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls". Gut. 54 (10): 1456–60. doi:10.1136/gut.2005.064808. PMC 1774703. PMID 15987793.
  35. ↑ Cohn JA, Neoptolemos JP, Feng J, Yan J, Jiang Z, Greenhalf W, McFaul C, Mountford R, Sommer SS (2005). "Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers". Hum. Mutat. 26 (4): 303–7. doi:10.1002/humu.20232. PMID 16134171.
  36. ↑ Bertin C, Pelletier AL, Vullierme MP, Bienvenu T, Rebours V, Hentic O, Maire F, Hammel P, Vilgrain V, Ruszniewski P, Lévy P (2012). "Pancreas divisum is not a cause of pancreatitis by itself but acts as a partner of genetic mutations". Am. J. Gastroenterol. 107 (2): 311–7. doi:10.1038/ajg.2011.424. PMID 22158025.
  37. ↑ Gelrud A, Sheth S, Banerjee S, Weed D, Shea J, Chuttani R, Howell DA, Telford JJ, Carr-Locke DL, Regan MM, Ellis L, Durie PR, Freedman SD (2004). "Analysis of cystic fibrosis gener product (CFTR) function in patients with pancreas divisum and recurrent acute pancreatitis". Am. J. Gastroenterol. 99 (8): 1557–62. doi:10.1111/j.1572-0241.2004.30834.x. PMID 15307877.
  38. ↑ Rosendahl J, Witt H, Szmola R, Bhatia E, Ozsvári B, Landt O, Schulz HU, Gress TM, Pfützer R, Löhr M, Kovacs P, Blüher M, Stumvoll M, Choudhuri G, Hegyi P, te Morsche RH, Drenth JP, Truninger K, Macek M, Puhl G, Witt U, Schmidt H, Büning C, Ockenga J, Kage A, Groneberg DA, Nickel R, Berg T, Wiedenmann B, Bödeker H, Keim V, Mössner J, Teich N, Sahin-Tóth M (2008). "Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis". Nat. Genet. 40 (1): 78–82. doi:10.1038/ng.2007.44. PMC 2650829. PMID 18059268.
  39. ↑ Masson E, Chen JM, Scotet V, Le Maréchal C, Férec C (2008). "Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis". Hum. Genet. 123 (1): 83–91. doi:10.1007/s00439-007-0459-3. PMID 18172691.
  40. ↑ LaRusch J, Lozano-Leon A, Stello K, Moore A, Muddana V, O'Connell M, Diergaarde B, Yadav D, Whitcomb DC (2015). "The Common Chymotrypsinogen C (CTRC) Variant G60G (C.180T) Increases Risk of Chronic Pancreatitis But Not Recurrent Acute Pancreatitis in a North American Population". Clin Transl Gastroenterol. 6: e68. doi:10.1038/ctg.2014.13. PMC 4418406. PMID 25569187.
  41. ↑ Beer S, Zhou J, Szabó A, Keiles S, Chandak GR, Witt H, Sahin-Tóth M (2013). "Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk". Gut. 62 (11): 1616–24. doi:10.1136/gutjnl-2012-303090. PMC 3660471. PMID 22942235.
  42. ↑ 42.0 42.1 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.
  43. ↑ Derikx MH, Kovacs P, Scholz M, Masson E, Chen JM, Ruffert C, Lichtner P, Te Morsche RH, Cavestro GM, Férec C, Drenth JP, Witt H, Rosendahl J (2015). "Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study". Gut. 64 (9): 1426–33. doi:10.1136/gutjnl-2014-307453. PMID 25253127.
  44. ↑ Masamune A, Nakano E, Hamada S, Kakuta Y, Kume K, Shimosegawa T (2015). "Common variants at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with chronic pancreatitis in Japan". Gut. 64 (8): 1345–6. doi:10.1136/gutjnl-2015-309802. PMID 26002935.
  45. ↑ 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.
  46. ↑ Teich N, Mössner J, Keim V (1998). "Mutations of the cationic trypsinogen in hereditary pancreatitis". Hum. Mutat. 12 (1): 39–43. doi:10.1002/(SICI)1098-1004(1998)12:1<39::AID-HUMU6>3.0.CO;2-P. PMID 9633818.
  47. ↑ Witt H, Sahin-Tóth M, Landt O, Chen JM, Kähne T, Drenth JP, Kukor Z, Szepessy E, Halangk W, Dahm S, Rohde K, Schulz HU, Le Maréchal C, Akar N, Ammann RW, Truninger K, Bargetzi M, Bhatia E, Castellani C, Cavestro GM, Cerny M, Destro-Bisol G, Spedini G, Eiberg H, Jansen JB, Koudova M, Rausova E, Macek M, Malats N, Real FX, Menzel HJ, Moral P, Galavotti R, Pignatti PF, Rickards O, Spicak J, Zarnescu NO, Böck W, Gress TM, Friess H, Ockenga J, Schmidt H, Pfützer R, Löhr M, Simon P, Weiss FU, Lerch MM, Teich N, Keim V, Berg T, Wiedenmann B, Luck W, Groneberg DA, Becker M, Keil T, Kage A, Bernardova J, Braun M, Güldner C, Halangk J, Rosendahl J, Witt U, Treiber M, Nickel R, Férec C (2006). "A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis". Nat. Genet. 38 (6): 668–73. doi:10.1038/ng1797. PMC 2746914. PMID 16699518.
  48. ↑ Santhosh S, Witt H, te Morsche RH, Nemoda Z, Molnár T, Pap A, Jansen JB, Drenth JP (2008). "A loss of function polymorphism (G191R) of anionic trypsinogen (PRSS2) confers protection against chronic pancreatitis". Pancreas. 36 (3): 317–20. doi:10.1097/MPA.0b013e31815db4b3. PMID 18362849.
  49. ↑ 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.
  50. ↑ Boocock GR, Morrison JA, Popovic M, Richards N, Ellis L, Durie PR, Rommens JM (2003). "Mutations in SBDS are associated with Shwachman-Diamond syndrome". Nat. Genet. 33 (1): 97–101. doi:10.1038/ng1062. PMID 12496757.
  51. ↑ Rötig A, Cormier V, Blanche S, Bonnefont JP, Ledeist F, Romero N, Schmitz J, Rustin P, Fischer A, Saudubray JM (1990). "Pearson's marrow-pancreas syndrome. A multisystem mitochondrial disorder in infancy". J. Clin. Invest. 86 (5): 1601–8. doi:10.1172/JCI114881. PMC 296909. PMID 2243133.
  52. ↑ Hopewell JW, Barnes DW, Robbins ME, Corp M, Sansom JM, Young CM, Wiernik G (1990). "The relative biological effectiveness of fractionated doses of fast neutrons (42 MeVd----Be) for normal tissues in the pig. II. Late effects on cutaneous and subcutaneous tissues". Br J Radiol. 63 (754): 760–70. doi:10.1259/0007-1285-63-754-760. PMID 2242473.
  53. ↑ Becher MW, Wills ML, Noll WW, Hurko O, Price DL (1999). "Kearns-Sayre syndrome with features of Pearson's marrow-pancreas syndrome and a novel 2905-base pair mitochondrial DNA deletion". Hum. Pathol. 30 (5): 577–81. PMID 10333230.
  54. ↑ Raeder H, Johansson S, Holm PI, Haldorsen IS, Mas E, Sbarra V, Nermoen I, Eide SA, Grevle L, Bjørkhaug L, Sagen JV, Aksnes L, Søvik O, Lombardo D, Molven A, Njølstad PR (2006). "Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction". Nat. Genet. 38 (1): 54–62. doi:10.1038/ng1708. PMID 16369531.
  55. ↑ Zenker M, Mayerle J, Lerch MM, Tagariello A, Zerres K, Durie PR, Beier M, Hülskamp G, Guzman C, Rehder H, Beemer FA, Hamel B, Vanlieferinghen P, Gershoni-Baruch R, Vieira MW, Dumic M, Auslender R, Gil-da-Silva-Lopes VL, Steinlicht S, Rauh M, Shalev SA, Thiel C, Ekici AB, Winterpacht A, Kwon YT, Varshavsky A, Reis A (2005). "Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome)". Nat. Genet. 37 (12): 1345–50. doi:10.1038/ng1681. PMID 16311597.

Template:WH Template:WS

Retrieved from "https://www.wikidoc.org/index.php?title=Hereditary_pancreatitis_pathophysiology&oldid=1435700"