Hereditary pancreatitis pathophysiology: Difference between revisions
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*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 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: | * 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 | ||
Revision as of 02:02, 16 January 2018
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2]
Overview
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:
- New mutations at different sites on PRSS1 gene may include:[3][5][6][7][8][9]
- Misfolding and intracellular retention of cationic trypsinogen
- Stabilization of trypsinogen, protecting against autocatalytic degradation
- Increases trypsin activation from trypsinogen
- Mutations in PRSS1 gene result in
- Premature activation of digestive enzymes resulting in:
- Pancreatic injury
- Immune system activation
- Acute pancreatitis
- Chronic pancreatitis
- Premature activation of digestive enzymes resulting in:
Mode of inheritance:
- Hereditary pancreatitis involves atleast 3 different patterns of inheritance:[10][11][12][13][14][15][16][17]
| 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:
- Serine protease 1 gene (PRSS1) encodes for trypsin-1 (cationic trypsinogen).
- 80% of patients with autosomal dominant hereditary pancreatitis have mutations in PRSS1 gene.[18][19][20][21][22][23]
- The most common mutations in PRSS1 include R122H and N29I.[11][12][18][22]
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.[19][24][25][8][26][27]
- 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.[16][17]
- SPINK variants are also found to be associated with:[28]
- Idiopathic pancreatitis
- Alcoholic pancreatitis
- Familial pancreatitis
- Tropical pancreatitis
Mutations in CFTR gene:
Mutations in CTRC gene:
Mutations in other genes:
Common mutations:
- The most common disease associated mutations in PRSS1 gene include:[11][12][29]
- R122H[11]
- N29I
- A16V
- Other genes may include:
- PRSS2, the anionic trypsinogen gene
Associated Conditions
Hereditary pancreatitis may be associated with following syndromes:
- Shwachman-Diamond syndrome (SDS)
- Pearson marrow pancreas syndrome
- CEL maturity-onset diabetes of the young (CEL-MODY)
- Johanson-Blizzard syndrome
Gross Pathology
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
- On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
References
- ↑ Whitcomb DC, Ulrich CD (1999). "Hereditary pancreatitis: new insights, new directions". Baillieres Best Pract Res Clin Gastroenterol. 13 (2): 253–63. PMID 11030605.
- ↑ Whitcomb DC (2010). "Genetic aspects of pancreatitis". Annu. Rev. Med. 61: 413–24. doi:10.1146/annurev.med.041608.121416. PMID 20059346.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 8.0 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.
- ↑ 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.
- ↑ 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.
- ↑ 11.0 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.
- ↑ 12.0 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 16.0 16.1 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.
- ↑ 17.0 17.1 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.
- ↑ 18.0 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.
- ↑ 19.0 19.1 DiMagno MJ, DiMagno EP (2005). "Chronic pancreatitis". Curr. Opin. Gastroenterol. 21 (5): 544–54. PMID 16093768.
- ↑ 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.
- ↑ 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.
- ↑ 22.0 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.