Hereditary pancreatitis
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Transcript of Hereditary pancreatitis
Whitcomb 2000
Pancreatic Diseases:Insights from Hereditary
PancreatitisWritten byWritten by
David C Whitcomb MD PhDDavid C Whitcomb MD PhDDepartment of Medicine, University Department of Medicine, University ofof Pittsburgh Pittsburgh
Educational Use ONLY
Whitcomb 2000
Hereditary Pancreatitis
� Hereditary pancreatitis Hereditary pancreatitis (HP) is an unusual form of (HP) is an unusual form of acute and chronic pancreatitis that runs in families. acute and chronic pancreatitis that runs in families. The risk of pancreatic cancer is >50 times normal.The risk of pancreatic cancer is >50 times normal.
� Although HP is only responsible for 2-3% of all Although HP is only responsible for 2-3% of all cases of chronic pancreatitis, study of this disease cases of chronic pancreatitis, study of this disease has revolutionized our understanding of pancreatic has revolutionized our understanding of pancreatic diseasesdiseases
PancreasPancreas
Whitcomb 2000
Discovery of the Pancreatitis Gene
ccaccaccagtcaggcacactctaccaccATGAATCCACTCCTGATCCTTACCTTTGT
GG/ACAGCTGC TCgtgagtatcatgccctgcctcaggccccaaccacccccccgttcctggccgaDNA
1. Family 2. Genetic Mapping 3. Mutation 4. Mechanism
Chromosome 7
HereditaryPancreatitisgene
Functional significancedetermined
Mutation in the trypsinogenDNA sequenceRecruitment
Trypsinogen
Whitcomb 2000
Linkage of HP to Chromosome 7q35
D7S
505
D7S
661
D7S
684
D7S
523
D7S
461
D7S
495
D7S
483
D7S
550
D7S
559-5
3
0
LO
D S
core
s
HP GENE
5
Whitcomb et al. GASTROENTEROLOGY 110:1975, 1996Whitcomb et al. GASTROENTEROLOGY 110:1975, 1996
0.00001
0.001
0.1
(P v
alue
)
0.01
0.00014
21
Markers on chromosome 7
HereditaryHereditaryPancreatitis Pancreatitis
GeneGene
Cystic Cystic FibrosisFibrosisGeneGene
Chromosome 7
TCRBTCRB
Whitcomb 2000
Cationic Trypsinogen GenectgatgcaagacccTGGGAagaggaaagctgCAggtgtgtttgtgcTGGGAggagtggtgaccctcacctcacagtcacctcctctctggatcctcgtgaggtataaagacgagtcct130801ccaccaccagtcaggcacactctaccaccATGAATCCACTCCTGATCCTTACCTTTGTGGCAGCTGCTCgtgagtatcatgccctgcctcaggccccaaccacccccccgttcctggccgaCAaatgcccttccattcttaccacctctcctcttttgactgtgctctgatattccgtttcctcCAtctggcatatctccttcccatcctccttgggctctttttaagtctCAcctgttcaccttctccttgacttcactcccaccactgtcattcatccatatccgagttgtggttggagaagcTGGGAagggggcCAggtggggctgtcccacgaaatgaagcagcaggcttcaggcttggctccgacagcaacagaatagcaccactatagctgctcctaacctcgaatgcacctggggaggttgaaaaattactcatgccagagactcagctctagaaattctaacttCAattgtctggggtagagcttgtgttctgggcttttaagcttccCAggtgatttttaatatttccagccatgcagccaaggttaagaattgctgtcctattggccaataacaaagtctacctttgttctgccaaagtgagcctgggggctgccctcaactctgccctgactgcacagatctgagctatgggggaaggtggtcatggccaggtctatgcagacagggggttttcctagcttggcaaaagaatcctgacaatccagggcccaaatagccaggggaagtacaCAggtgatgaataaaagagagaagcactcagTGGGAgagacaaccacatcccaactcctatcccactggaagcattgtgaggacattccttgcgacttcagcctggtgaccccaggagagctcggatcctccgcagggtacctagctatgtgccctgcaggcacagagactTGGGAgccacaggcagtgatgatcaccaggggtggcagagctccctcccttgcctagcctcactgtgcttgttaaggatttctaattagcagaaagcaatcacaggcTGGGAgcgccacccctaacatgctattgacttgccttctcccttcccatctccactcCAgTTGCTGCCCCCTTTGATGATGATGACAAGATCGTTGGGGGCTACAACTGTGAGGAGAATTCTGTCCCCTACCAGGTGTCCCTGAATTCTGGCTACCACTTCTGTGGTGGCTCCCTCATCAACGAACAGTGGGTGGTATCAGCAGGCCACTGCTACAAGTcgtaagtgtggggcccccgactgcaaagctcccggccagtctgccTGGGAgagcttggcttcagcccagggaactactgaggttgggtaagatggaTGGGAgaggtggtggagaagaaaacttgttggCAgctgcggactctccagagcagagagtgaacacaagacaggaacctctcacacccaggcaaatccatgaaacagcaagggttgtggtcataaaagcaggcagggatgatcttggggtggtgagagctagtgagaaaagcaggcaagtatcttttgctggttagctacacattaaagccaactaagaaagactttttaaaaataCAgatgcctttgtcctatcccagggcaattaagtcaaaattttcaggaagagggtgtgaatatcagtgagaattttacactctacctctgctaactgtagagtgtatagacagagctgagaactgctgcctacaccaagaactctcaaacctgagtatgcatcagaacgccctgcaggcttgttaaggcacaaatcactgggccccttccccaaggttctgatcagtaggtgggggtaaggaccaagaattcacatttctaacaagttcccaggagatgctaatgctatggctacccttggattagattacacagaagggtggttctcaccaggccaagaatggagggaggaacaggcactgtgcaCAgttggcaaaggcctggggtgaagaatgcTGGGAaaacttcaaggagctccttgtgcccacagtgctagtgactgtggagattgTGGGAaagagtctggggaggcaggttgaggagcagcctctggTGGGAtccctttgactcttccccaccccactaccaccaacctctggagcagataggtcctgggtctcataccttcactgacccacatccctctgctgcccatgcgatatggccacacaccccaccccatgcctccagagctgtccatgagcagagagcttgaggaacctggggaaggTGGGAtaggtgccctggctgTGGGAgaaggtcttcaccatgcctgccctgcccatcagCCGCATCCAGGTGAGACTGGGAGAGCACAACATCGAAGTCCTGGAGGGGAATGAGCAGTTCATCAATGCAGCCAAGATCATCCGCCACCCCCAATACGACAGGAAGACTCTGAACAATGACATCATGTTAATCAAGCTCTCCTCACGTGCAGTAATCAACGCCCGCGTGTCCACCATCTCTCTGCCCACCGCCCCTCCAGCCACTGGCACGAAGTGCCTCATCTCTGGCTGGGGCAACACTGCGAGCTCTGGCGgtgagTGGGAcccttagtccttctacttccctccatcctcacaatttccagaacaaaccatgccccttaacttgaatcctctcacctccaggcttaagacacatttcgagtgcccattacacacagactctgcactgggcaccagagagatgcaaactatcaaggacttggctcctaaaatcaagagacaggaCAaatggagaacttgatatgatcacatctTGGGAggggttcaacaatgatcattcTGGGAactaaaagccagagtctcttgccaggacttatgttctggagtcctctccaggggctgtgttcctcttcagttttccatccaagattattgtctccttctctggcctgacccacatttctacttcctttgatctcttcctgatcctcacagCCGACTACCCAGACGAGCTGCAGTGCCTGGACGCTCCTGTGCTGAGCCAGGCTAAGTGTGAAGCCTCCTACCCTGGAAAGATTACCAGCAACATGTTCTGTGTGGGCTTCCTTGAGGGAGGCAAGGATTCATGTCAGgtgatttgaccaacccttcccatgctgaggctcccactgatacctaggccccaccagggaaaaggatttgaactcaaaaggtggtggggctgaggaggctccctgcagtgcccacatggagaagtgaggaagactcccttgggctgcatcttgtctgcttaggaagaacagagaatgggccaccatgagaaggacatggagccacagagctggctggaaaggggtcttttaaggttcagagtaaatgtagctatattcctcctccatctctccatacaacttgtcccttcttccccccagGGTGATTCTGGTGGCCCTGTGGTCTGCAATGGACAGCTCCAAGGAGTTGTCTCCTGGGGTGATGGCTGTGCCCAGAAGAACAAGCCTGGAGTCTACACCAAGGTCTACAACTATGTGAAATGGATTAAGAACACCATAGCTGCCAACAGCTAAagcccccagtatctcttcagtctctataccaataaagtgaccctgttctcactgtctgtgtctgtgcctgctccctctcactccttcacactggaaagcatcctccaatttcaggttagacacgactgtcccctttaaaggtaagcagagcccc
Whitcomb 2000
HP is caused by “Super-Trypsin”
Whitcomb et al, Whitcomb et al, Nature Genetics Nature Genetics 19961996
Trypsin
Active trypsin in the pancreaswill cause the pancreas to digestitself.
Normally, the pancreas is protected because active trypsin will destroy itself by cutting at R117. This will split the trypsin and inactivate it.
In HP, R117 is mutated to H117. This creates a “super-trypsin” that cannot be inactivated and leads to acute pancreatitis.
Whitcomb 2000
Conclusions
� Discovery of the Discovery of the hereditary pancreatitis hereditary pancreatitis gene is an example of how genetic research gene is an example of how genetic research can revolutionize our understanding of a can revolutionize our understanding of a disease process. disease process.
Whitcomb 2000
Pancreatitis
� PancreasPancreas - - an organ that makes an organ that makes bicarbonatebicarbonate to nutralize gastric acid, to nutralize gastric acid, enzymesenzymes to digest the contents of a meal and to digest the contents of a meal and insulininsulin to signal the body to to signal the body to store ingested nutrients.store ingested nutrients.
� Acute PancreatitisAcute Pancreatitis - An acute, potentially life-threatening condition - An acute, potentially life-threatening condition presenting with severe abdominal pain in which the pancreas appears to presenting with severe abdominal pain in which the pancreas appears to digest itself. It is usually caused by gallstones, alcohol or is idiopathic.digest itself. It is usually caused by gallstones, alcohol or is idiopathic.
� Chronic Pancreatitis Chronic Pancreatitis - an- an irreversible scarring of the pancreas with irreversible scarring of the pancreas with permanent loss of pancreatic function that typically causes unrelenting permanent loss of pancreatic function that typically causes unrelenting abdominal pain.abdominal pain.
� Hereditary Pancreatitis Hereditary Pancreatitis - a unusual form of acute and chronic pancreatitis - a unusual form of acute and chronic pancreatitis that runs in families. The risk of pancreatic cancer is >50 times normal.that runs in families. The risk of pancreatic cancer is >50 times normal.
PancreasPancreas
Whitcomb 2000
Fail-safe Trypsin Inactivation
Trypsinogen
PSTIPSTI TrypsinTrypsinTrypsinTrypsin
Trypsin (wt)Trypsin (wt)
Proenzymes Enzymes
Autodigestion
+
-
(Autoactivation)
-
-
-
Whitcomb et al, Whitcomb et al, Nature Genetics Nature Genetics 19961996
-Trypsin
HPHP
Whitcomb 2000
1) Proenzymes1) Proenzymes
2) Low calcium2) Low calcium
3) Compartmentalized3) Compartmentalized
4) Trypsin inhibitor4) Trypsin inhibitor
5) 5) Zymogen Zymogen autolysisautolysis
6) Remote activation6) Remote activation
7) 7) αα11- antitrypsin, - antitrypsin,
β β22 microglobulinmicroglobulin
Super-trypsin in HP
NucleusNucleus
R.E.R.R.E.R.
EnterokinaseEnterokinase(normal trypsin trigger)(normal trypsin trigger)
LysosomesLysosomes
ZymogensZymogens(digestive(digestive enzymes)enzymes)
CVZ
TrypsinTrypsin
GolgiGolgi
Pancreatic Acinar CellPancreatic Acinar Cell
Pancreas Intestine
Premature Activation
Normal Normal (autolysis)(autolysis)
HereditaryHereditaryPancreatitisPancreatitis(trypsin (trypsin activates activates cascade)cascade)
Whitcomb 2000
Implications of the HP Discovery
� Acute pancreatitisAcute pancreatitis starts with trypsin activation within the starts with trypsin activation within the pancreatic acinar cells - pancreatic acinar cells - not from digestive enzymes leaking not from digestive enzymes leaking from injured pancreatic ducts!from injured pancreatic ducts!
� Chronic pancreatitisChronic pancreatitis develops from multiple attacks of develops from multiple attacks of acute pancreatitis - acute pancreatitis - not from duct obstruction by calcium.not from duct obstruction by calcium.
� Pancreatic Cancer Pancreatic Cancer - occurs from chronic inflammation of - occurs from chronic inflammation of the pancreas - the pancreas - not from an oncogenenot from an oncogene
� TherapyTherapy should be directed at preventing excessive, should be directed at preventing excessive, premature trypsin activation.premature trypsin activation.