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

Family Tree (S-Family)

I

II

III

IV

V

VI

MaleFemaleAffectedCarrier

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.

Whitcomb 2000

** WARNING **

Educational Use Only

No portion of this presentation is to be used without the express written consent of Dr Whitcomb