Hereditary pancreatitis pathophysiology: Difference between revisions
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*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 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> | ||
*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 may include | |||
** Misfolding and intracellular retention of cationic trypsinogen | |||
** Stabilization of trypsinogen, protecting against autocatalytic degradation | |||
** Increases trypsin activation from trypsinogen | |||
===Mode of inheritance:=== | ===Mode of inheritance:=== | ||
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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:
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:
- Mutations at different sites on PRSS1 gene may include
- Misfolding and intracellular retention of cationic trypsinogen
- Stabilization of trypsinogen, protecting against autocatalytic degradation
- Increases trypsin activation from trypsinogen
Mode of inheritance:
- Hereditary pancreatitis involves atleast 3 different patterns of inheritance:[5][6][7][8][9][10][11][12]
| 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.[13][14][15][16][17][18]
- The most common mutations in PRSS1 include R122H and N29I.[6][7][13][17]
Mutations in SPINK1 gene:
Mutations in CFTR gene:
Mutations in CTRC gene:
Mutations in other genes:
Common mutations:
- The most common disease associated mutations in PRSS1 gene include:[6][7][19]
- R122H[6]
- 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.
- ↑ 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.
- ↑ 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.
- ↑ 6.0 6.1 6.2 6.3 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.
- ↑ 7.0 7.1 7.2 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.
- ↑ 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.
- ↑ 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.
- ↑ 13.0 13.1 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.
- ↑ 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.
- ↑ 17.0 17.1 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.
- ↑ 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.