Let me know what you think about this.....thanks....Mark

[Guest guest]

RESEARCH LETTER

Mutation in the SPINK1 Trypsin Inhibitor Gene, Alcohol Use, and Chronic

Pancreatitis

To the Editor: In industrialized countries, chronic pancreatitis (CP) is caused

by long-term alcohol abuse in about 70% of cases, whereas the cause is generally

unknown in the other 30% of patients. Furthermore, it is unclear how alcohol use

may lead to CP, and wide variation exists among individuals in their

susceptibility to alcoholic CP (ACP). Only a minority of frequent drinkers

develop ACP.1 However, genetic factors may also affect the pathogenesis of ACP.

Recently, an N34S mutation in the pancreatic secretory serine protease inhibitor

Kazal type 1 (SPINK1) gene was found in 18 of 96 patients with idiopathic or

hereditary CP.2 Therefore, in such patients with ACP, a prominent pathogenic

role of trypsin activity in the pancreatic acinar cell may be suspected.

Methods

We investigated the frequency of the N34S mutation of SPINK1 in 274 patients

with ACP who were admitted to 1 of our 6 institutions between 1998 and 2000, as

well as 98 patients with chronic alcoholism who presented with liver disease or

for treatment of alcohol addiction but were without clinical evidence of

pancreatitis, and 540 healthy controls (ie, 143 cord blood samples taken

following a normal obstetric delivery and blood samples from 397 medical

students and staff). Diagnosis of ACP was based on a typical history and at

least 1 of the following criteria: pancreatic calcifications, characteristic

histologic findings, ductal alterations, or persistent exocrine insufficiency.

Patients with a family history of CP were excluded. Alcoholism was defined as an

ethanol intake of more than 80 g/d in men and more than 60 g/d in women for at

least 2 years.1 Forty-seven patients and 210 controls were from the United

Kingdom, 173 patients and 428 controls were from Germany, and 54 patients were

from Switzerland. Written or oral informed consent was obtained. The N34S

mutation was analyzed as described previously.2 Statistical analysis was

performed using cross-tabulation with the Fisher exact test (SPSS version 9.0;

SPSS Inc, Chicago, Ill).

Results

The N34S mutation was detected in 16 (5.8%) of 274 patients with ACP. All these

patients were heterozygous for the mutation. A heterozygous N34S mutation was

found in only 1 (1.0%) of 98 patients with alcoholism without ACP and in 4

(0.8%) of 540 controls. The mutation was significantly more prevalent in

patients with ACP vs patients with alcoholism but without CP (P = .004) and vs

controls (P<.001). There were no significant differences in the frequency of

N34S between controls and patients with alcoholism without CP or among the

different ethnicities.

Comment

The SPINK1 N34S mutation appears to be a genetic risk factor for ACP. Studies

investigating the cationic trypsinogen,3 1-antitrypsin, alcohol dehydrogenase,

and HLA antigen have yielded negative or conflicting results,4 and a previously

demonstrated association between cystic fibrosis mutations and CP was not

confirmed in patients with ACP.5

Our results suggest that the pancreatic protease–protease inhibitor system plays

a role in pathogenesis of ACP. Patients with chronic alcoholism have been found

to have a significantly higher ratio of trypsinogen to trypsin inhibitor in

their pancreatic fluids compared with controls without alcholism.6 This may

indicate a weakening of the defense mechanism provided by trypsin inhibitor

against premature zymogen activation. Because the majority of patients with

alcoholism do not develop CP, our findings support the hypothesis that a

combination of both exogenous and genetic factors may predispose to CP.

Heiko Witt, MD

Werner Luck, MD

Becker, MD

Department of Pediatrics

Böhmig, MD

Department of Medicine

s Kage, MD

Institute of Laboratory Medicine and Pathobiochemistry

Humboldt University

Berlin, Germany

Kaspar Truninger, MD

Rudolf W. Ammann, MD

Department of Medicine

Division of Gastroenterology

University Hospital

Zürich, Switzerland

O'Reilly, MRCS

Kingsnorth, FRCS, FACS

Department of Surgery

Derriford Hospital

Plymouth, England

Hans-Ulrich Schulz, MD

Walter Halangk, PhD

Department of Surgery

Otto-von-Guericke University Magdeburg

Volker Kielstein, MD

Outpatient Clinic for Addiction Diseases

Magdeburg, Germany

Wolfram T. Knoefel, MD

Department of Surgery

Universitätsklinikum Eppendorf

Hamburg, Germany

Niels Teich, MD

Volker Keim, MD

Department of Medicine

University of Leipzig

Leipzig, Germany

1. Ammann RW. A clinically based classification system for alcoholic chronic

pancreatitis: summary of an international workshop on chronic pancreatitis.

Pancreas. 1997;14:215-221. MEDLINE

2. Witt H, Luck W, Hennies HC, et al. Mutations in the gene encoding the serine

protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat

Genet. 2000;25:213-216. MEDLINE

3. Teich N, Mössner J, Keim V. Screening for mutations of the cationic

trypsinogen gene: are they of relevance in chronic alcoholic pancreatitis? Gut.

1999;44:413-416. MEDLINE

4. Haber P, J, Apte M, Korsten M, Pirola A. Individual susceptibility to

alcoholic pancreatitis: still an enigma. J Lab Clin Med. 1995;125:305-312.

MEDLINE

5. Norton ID, Apte MV, Dixson H, et al. Cystic fibrosis genotypes and alcoholic

pancreatitis. J Gastroenterol Hepatol. 1998;13:496-499. MEDLINE

6. Rinderknecht H, Stace NH, Renner IG. Effects of alcohol abuse on exocrine

pancreatic secretion in man. Dig Dis Sci. 1985;50:65-71.

Funding/Support: This work was supported by a grant from Sonnenfeld-Stiftung,

Berlin, Germany.

Letters Information

Guidelines for Letters

Letters Section Editors: J. Lurie, MD, PhD, Senior Editor; Jody W.

Zylke, MD, Contributing Editor.

Mark E. Armstrong

www.top5plus5.com

NW Chapter Rep

Pancreatitis Association, International

[Guest guest]

Mark E. Armstrong

NW Rep, PAI

www.top5plus5.com

casca@...

Let me know what you think about this.....thanks....Mark

RESEARCH LETTER

Mutation in the SPINK1 Trypsin Inhibitor Gene, Alcohol Use, and Chronic

Pancreatitis

To the Editor: In industrialized countries, chronic pancreatitis (CP) is

caused by long-term alcohol abuse in about 70% of cases, whereas the cause is

generally unknown in the other 30% of patients. Furthermore, it is unclear how

alcohol use may lead to CP, and wide variation exists among individuals in their

susceptibility to alcoholic CP (ACP). Only a minority of frequent drinkers

develop ACP.1 However, genetic factors may also affect the pathogenesis of ACP.

Recently, an N34S mutation in the pancreatic secretory serine protease

inhibitor Kazal type 1 (SPINK1) gene was found in 18 of 96 patients with

idiopathic or hereditary CP.2 Therefore, in such patients with ACP, a prominent

pathogenic role of trypsin activity in the pancreatic acinar cell may be

suspected.

Methods

We investigated the frequency of the N34S mutation of SPINK1 in 274 patients

with ACP who were admitted to 1 of our 6 institutions between 1998 and 2000, as

well as 98 patients with chronic alcoholism who presented with liver disease or

for treatment of alcohol addiction but were without clinical evidence of

pancreatitis, and 540 healthy controls (ie, 143 cord blood samples taken

following a normal obstetric delivery and blood samples from 397 medical

students and staff). Diagnosis of ACP was based on a typical history and at

least 1 of the following criteria: pancreatic calcifications, characteristic

histologic findings, ductal alterations, or persistent exocrine insufficiency.

Patients with a family history of CP were excluded. Alcoholism was defined as an

ethanol intake of more than 80 g/d in men and more than 60 g/d in women for at

least 2 years.1 Forty-seven patients and 210 controls were from the United

Kingdom, 173 patients and 428 controls were from Germany, and 54 patients were

from Switzerland. Written or oral informed consent was obtained. The N34S

mutation was analyzed as described previously.2 Statistical analysis was

performed using cross-tabulation with the Fisher exact test (SPSS version 9.0;

SPSS Inc, Chicago, Ill).

Results

The N34S mutation was detected in 16 (5.8%) of 274 patients with ACP. All

these patients were heterozygous for the mutation. A heterozygous N34S mutation

was found in only 1 (1.0%) of 98 patients with alcoholism without ACP and in 4

(0.8%) of 540 controls. The mutation was significantly more prevalent in

patients with ACP vs patients with alcoholism but without CP (P = .004) and vs

controls (P<.001). There were no significant differences in the frequency of

N34S between controls and patients with alcoholism without CP or among the

different ethnicities.

Comment

The SPINK1 N34S mutation appears to be a genetic risk factor for ACP. Studies

investigating the cationic trypsinogen,3 1-antitrypsin, alcohol dehydrogenase,

and HLA antigen have yielded negative or conflicting results,4 and a previously

demonstrated association between cystic fibrosis mutations and CP was not

confirmed in patients with ACP.5

Our results suggest that the pancreatic protease–protease inhibitor system

plays a role in pathogenesis of ACP. Patients with chronic alcoholism have been

found to have a significantly higher ratio of trypsinogen to trypsin inhibitor

in their pancreatic fluids compared with controls without alcholism.6 This may

indicate a weakening of the defense mechanism provided by trypsin inhibitor

against premature zymogen activation. Because the majority of patients with

alcoholism do not develop CP, our findings support the hypothesis that a

combination of both exogenous and genetic factors may predispose to CP.

Heiko Witt, MD

Werner Luck, MD

Becker, MD

Department of Pediatrics

Böhmig, MD

Department of Medicine

s Kage, MD

Institute of Laboratory Medicine and Pathobiochemistry

Humboldt University

Berlin, Germany

Kaspar Truninger, MD

Rudolf W. Ammann, MD

Department of Medicine

Division of Gastroenterology

University Hospital

Zürich, Switzerland

O'Reilly, MRCS

Kingsnorth, FRCS, FACS

Department of Surgery

Derriford Hospital

Plymouth, England

Hans-Ulrich Schulz, MD

Walter Halangk, PhD

Department of Surgery

Otto-von-Guericke University Magdeburg

Volker Kielstein, MD

Outpatient Clinic for Addiction Diseases

Magdeburg, Germany

Wolfram T. Knoefel, MD

Department of Surgery

Universitätsklinikum Eppendorf

Hamburg, Germany

Niels Teich, MD

Volker Keim, MD

Department of Medicine

University of Leipzig

Leipzig, Germany

1. Ammann RW. A clinically based classification system for alcoholic chronic

pancreatitis: summary of an international workshop on chronic pancreatitis.

Pancreas. 1997;14:215-221. MEDLINE

2. Witt H, Luck W, Hennies HC, et al. Mutations in the gene encoding the

serine protease inhibitor, Kazal type 1 are associated with chronic

pancreatitis. Nat Genet. 2000;25:213-216. MEDLINE

3. Teich N, Mössner J, Keim V. Screening for mutations of the cationic

trypsinogen gene: are they of relevance in chronic alcoholic pancreatitis? Gut.

1999;44:413-416. MEDLINE

4. Haber P, J, Apte M, Korsten M, Pirola A. Individual susceptibility

to alcoholic pancreatitis: still an enigma. J Lab Clin Med. 1995;125:305-312.

MEDLINE

5. Norton ID, Apte MV, Dixson H, et al. Cystic fibrosis genotypes and

alcoholic pancreatitis. J Gastroenterol Hepatol. 1998;13:496-499. MEDLINE

6. Rinderknecht H, Stace NH, Renner IG. Effects of alcohol abuse on exocrine

pancreatic secretion in man. Dig Dis Sci. 1985;50:65-71.

Funding/Support: This work was supported by a grant from Sonnenfeld-Stiftung,

Berlin, Germany.

Letters Information

Guidelines for Letters

Letters Section Editors: J. Lurie, MD, PhD, Senior Editor; Jody W.

Zylke, MD, Contributing Editor.

Mark E. Armstrong

www.top5plus5.com

NW Chapter Rep

Pancreatitis Association, International

[Guest guest]

Mark E. Armstrong

NW Rep, PAI

www.top5plus5.com

casca@...

Let me know what you think about this.....thanks....Mark

RESEARCH LETTER

Mutation in the SPINK1 Trypsin Inhibitor Gene, Alcohol Use, and Chronic

Pancreatitis

To the Editor: In industrialized countries, chronic pancreatitis (CP) is

caused by long-term alcohol abuse in about 70% of cases, whereas the cause is

generally unknown in the other 30% of patients. Furthermore, it is unclear how

alcohol use may lead to CP, and wide variation exists among individuals in their

susceptibility to alcoholic CP (ACP). Only a minority of frequent drinkers

develop ACP.1 However, genetic factors may also affect the pathogenesis of ACP.

Recently, an N34S mutation in the pancreatic secretory serine protease

inhibitor Kazal type 1 (SPINK1) gene was found in 18 of 96 patients with

idiopathic or hereditary CP.2 Therefore, in such patients with ACP, a prominent

pathogenic role of trypsin activity in the pancreatic acinar cell may be

suspected.

Methods

We investigated the frequency of the N34S mutation of SPINK1 in 274 patients

with ACP who were admitted to 1 of our 6 institutions between 1998 and 2000, as

well as 98 patients with chronic alcoholism who presented with liver disease or

for treatment of alcohol addiction but were without clinical evidence of

pancreatitis, and 540 healthy controls (ie, 143 cord blood samples taken

following a normal obstetric delivery and blood samples from 397 medical

students and staff). Diagnosis of ACP was based on a typical history and at

least 1 of the following criteria: pancreatic calcifications, characteristic

histologic findings, ductal alterations, or persistent exocrine insufficiency.

Patients with a family history of CP were excluded. Alcoholism was defined as an

ethanol intake of more than 80 g/d in men and more than 60 g/d in women for at

least 2 years.1 Forty-seven patients and 210 controls were from the United

Kingdom, 173 patients and 428 controls were from Germany, and 54 patients were

from Switzerland. Written or oral informed consent was obtained. The N34S

mutation was analyzed as described previously.2 Statistical analysis was

performed using cross-tabulation with the Fisher exact test (SPSS version 9.0;

SPSS Inc, Chicago, Ill).

Results

The N34S mutation was detected in 16 (5.8%) of 274 patients with ACP. All

these patients were heterozygous for the mutation. A heterozygous N34S mutation

was found in only 1 (1.0%) of 98 patients with alcoholism without ACP and in 4

(0.8%) of 540 controls. The mutation was significantly more prevalent in

patients with ACP vs patients with alcoholism but without CP (P = .004) and vs

controls (P<.001). There were no significant differences in the frequency of

N34S between controls and patients with alcoholism without CP or among the

different ethnicities.

Comment

The SPINK1 N34S mutation appears to be a genetic risk factor for ACP. Studies

investigating the cationic trypsinogen,3 1-antitrypsin, alcohol dehydrogenase,

and HLA antigen have yielded negative or conflicting results,4 and a previously

demonstrated association between cystic fibrosis mutations and CP was not

confirmed in patients with ACP.5

Our results suggest that the pancreatic protease–protease inhibitor system

plays a role in pathogenesis of ACP. Patients with chronic alcoholism have been

found to have a significantly higher ratio of trypsinogen to trypsin inhibitor

in their pancreatic fluids compared with controls without alcholism.6 This may

indicate a weakening of the defense mechanism provided by trypsin inhibitor

against premature zymogen activation. Because the majority of patients with

alcoholism do not develop CP, our findings support the hypothesis that a

combination of both exogenous and genetic factors may predispose to CP.

Heiko Witt, MD

Werner Luck, MD

Becker, MD

Department of Pediatrics

Böhmig, MD

Department of Medicine

s Kage, MD

Institute of Laboratory Medicine and Pathobiochemistry

Humboldt University

Berlin, Germany

Kaspar Truninger, MD

Rudolf W. Ammann, MD

Department of Medicine

Division of Gastroenterology

University Hospital

Zürich, Switzerland

O'Reilly, MRCS

Kingsnorth, FRCS, FACS

Department of Surgery

Derriford Hospital

Plymouth, England

Hans-Ulrich Schulz, MD

Walter Halangk, PhD

Department of Surgery

Otto-von-Guericke University Magdeburg

Volker Kielstein, MD

Outpatient Clinic for Addiction Diseases

Magdeburg, Germany

Wolfram T. Knoefel, MD

Department of Surgery

Universitätsklinikum Eppendorf

Hamburg, Germany

Niels Teich, MD

Volker Keim, MD

Department of Medicine

University of Leipzig

Leipzig, Germany

1. Ammann RW. A clinically based classification system for alcoholic chronic

pancreatitis: summary of an international workshop on chronic pancreatitis.

Pancreas. 1997;14:215-221. MEDLINE

2. Witt H, Luck W, Hennies HC, et al. Mutations in the gene encoding the

serine protease inhibitor, Kazal type 1 are associated with chronic

pancreatitis. Nat Genet. 2000;25:213-216. MEDLINE

3. Teich N, Mössner J, Keim V. Screening for mutations of the cationic

trypsinogen gene: are they of relevance in chronic alcoholic pancreatitis? Gut.

1999;44:413-416. MEDLINE

4. Haber P, J, Apte M, Korsten M, Pirola A. Individual susceptibility

to alcoholic pancreatitis: still an enigma. J Lab Clin Med. 1995;125:305-312.

MEDLINE

5. Norton ID, Apte MV, Dixson H, et al. Cystic fibrosis genotypes and

alcoholic pancreatitis. J Gastroenterol Hepatol. 1998;13:496-499. MEDLINE

6. Rinderknecht H, Stace NH, Renner IG. Effects of alcohol abuse on exocrine

pancreatic secretion in man. Dig Dis Sci. 1985;50:65-71.

Funding/Support: This work was supported by a grant from Sonnenfeld-Stiftung,

Berlin, Germany.

Letters Information

Guidelines for Letters

Letters Section Editors: J. Lurie, MD, PhD, Senior Editor; Jody W.

Zylke, MD, Contributing Editor.

Mark E. Armstrong

www.top5plus5.com

NW Chapter Rep

Pancreatitis Association, International

[Guest guest]

Mark E. Armstrong

NW Rep, PAI

www.top5plus5.com

casca@...

Let me know what you think about this.....thanks....Mark

RESEARCH LETTER

Mutation in the SPINK1 Trypsin Inhibitor Gene, Alcohol Use, and Chronic

Pancreatitis

To the Editor: In industrialized countries, chronic pancreatitis (CP) is

caused by long-term alcohol abuse in about 70% of cases, whereas the cause is

generally unknown in the other 30% of patients. Furthermore, it is unclear how

alcohol use may lead to CP, and wide variation exists among individuals in their

susceptibility to alcoholic CP (ACP). Only a minority of frequent drinkers

develop ACP.1 However, genetic factors may also affect the pathogenesis of ACP.

Recently, an N34S mutation in the pancreatic secretory serine protease

inhibitor Kazal type 1 (SPINK1) gene was found in 18 of 96 patients with

idiopathic or hereditary CP.2 Therefore, in such patients with ACP, a prominent

pathogenic role of trypsin activity in the pancreatic acinar cell may be

suspected.

Methods

We investigated the frequency of the N34S mutation of SPINK1 in 274 patients

with ACP who were admitted to 1 of our 6 institutions between 1998 and 2000, as

well as 98 patients with chronic alcoholism who presented with liver disease or

for treatment of alcohol addiction but were without clinical evidence of

pancreatitis, and 540 healthy controls (ie, 143 cord blood samples taken

following a normal obstetric delivery and blood samples from 397 medical

students and staff). Diagnosis of ACP was based on a typical history and at

least 1 of the following criteria: pancreatic calcifications, characteristic

histologic findings, ductal alterations, or persistent exocrine insufficiency.

Patients with a family history of CP were excluded. Alcoholism was defined as an

ethanol intake of more than 80 g/d in men and more than 60 g/d in women for at

least 2 years.1 Forty-seven patients and 210 controls were from the United

Kingdom, 173 patients and 428 controls were from Germany, and 54 patients were

from Switzerland. Written or oral informed consent was obtained. The N34S

mutation was analyzed as described previously.2 Statistical analysis was

performed using cross-tabulation with the Fisher exact test (SPSS version 9.0;

SPSS Inc, Chicago, Ill).

Results

The N34S mutation was detected in 16 (5.8%) of 274 patients with ACP. All

these patients were heterozygous for the mutation. A heterozygous N34S mutation

was found in only 1 (1.0%) of 98 patients with alcoholism without ACP and in 4

(0.8%) of 540 controls. The mutation was significantly more prevalent in

patients with ACP vs patients with alcoholism but without CP (P = .004) and vs

controls (P<.001). There were no significant differences in the frequency of

N34S between controls and patients with alcoholism without CP or among the

different ethnicities.

Comment

The SPINK1 N34S mutation appears to be a genetic risk factor for ACP. Studies

investigating the cationic trypsinogen,3 1-antitrypsin, alcohol dehydrogenase,

and HLA antigen have yielded negative or conflicting results,4 and a previously

demonstrated association between cystic fibrosis mutations and CP was not

confirmed in patients with ACP.5

Our results suggest that the pancreatic protease–protease inhibitor system

plays a role in pathogenesis of ACP. Patients with chronic alcoholism have been

found to have a significantly higher ratio of trypsinogen to trypsin inhibitor

in their pancreatic fluids compared with controls without alcholism.6 This may

indicate a weakening of the defense mechanism provided by trypsin inhibitor

against premature zymogen activation. Because the majority of patients with

alcoholism do not develop CP, our findings support the hypothesis that a

combination of both exogenous and genetic factors may predispose to CP.

Heiko Witt, MD

Werner Luck, MD

Becker, MD

Department of Pediatrics

Böhmig, MD

Department of Medicine

s Kage, MD

Institute of Laboratory Medicine and Pathobiochemistry

Humboldt University

Berlin, Germany

Kaspar Truninger, MD

Rudolf W. Ammann, MD

Department of Medicine

Division of Gastroenterology

University Hospital

Zürich, Switzerland

O'Reilly, MRCS

Kingsnorth, FRCS, FACS

Department of Surgery

Derriford Hospital

Plymouth, England

Hans-Ulrich Schulz, MD

Walter Halangk, PhD

Department of Surgery

Otto-von-Guericke University Magdeburg

Volker Kielstein, MD

Outpatient Clinic for Addiction Diseases

Magdeburg, Germany

Wolfram T. Knoefel, MD

Department of Surgery

Universitätsklinikum Eppendorf

Hamburg, Germany

Niels Teich, MD

Volker Keim, MD

Department of Medicine

University of Leipzig

Leipzig, Germany

1. Ammann RW. A clinically based classification system for alcoholic chronic

pancreatitis: summary of an international workshop on chronic pancreatitis.

Pancreas. 1997;14:215-221. MEDLINE

2. Witt H, Luck W, Hennies HC, et al. Mutations in the gene encoding the

serine protease inhibitor, Kazal type 1 are associated with chronic

pancreatitis. Nat Genet. 2000;25:213-216. MEDLINE

3. Teich N, Mössner J, Keim V. Screening for mutations of the cationic

trypsinogen gene: are they of relevance in chronic alcoholic pancreatitis? Gut.

1999;44:413-416. MEDLINE

4. Haber P, J, Apte M, Korsten M, Pirola A. Individual susceptibility

to alcoholic pancreatitis: still an enigma. J Lab Clin Med. 1995;125:305-312.

MEDLINE

5. Norton ID, Apte MV, Dixson H, et al. Cystic fibrosis genotypes and

alcoholic pancreatitis. J Gastroenterol Hepatol. 1998;13:496-499. MEDLINE

6. Rinderknecht H, Stace NH, Renner IG. Effects of alcohol abuse on exocrine

pancreatic secretion in man. Dig Dis Sci. 1985;50:65-71.

Funding/Support: This work was supported by a grant from Sonnenfeld-Stiftung,

Berlin, Germany.

Letters Information

Guidelines for Letters

Letters Section Editors: J. Lurie, MD, PhD, Senior Editor; Jody W.

Zylke, MD, Contributing Editor.

Mark E. Armstrong

www.top5plus5.com

NW Chapter Rep

Pancreatitis Association, International