Clinical evaluation of the M-ANNHEIM classification: Development of the M-ANNHEIM-Surgery-Score as a new tool to monitor patients with chronic pancreatitis.

OBJECTIVES: The M-ANNHEIM classification of chronic pancreatitis (CP) stratifies degrees of disease severity according to the M-ANNHEIM-Severity-Score. We aimed to demonstrate the clinical usefulness of the M-ANNHEIM-Severity-Score in quantifying and predicting the frequency of pancreatic surgery, and to establish the M-ANNHEIM-Surgery-Score as a simplified system for patient surveillance regarding the demand of pancreatic surgery. METHODS: We performed a retrospective, cross-sectional study with 741 CP patients (Mannheim/Germany, n = 537; Gießen/Germany, n = 100; Donetsk/Ukraine, n = 104) categorized according to the M-ANNHEIM classification. RESULTS: We observed a significantly higher M-ANNHEIM-Severity-Score in patients that were classified within 7 days preceding pancreatic surgery than in individuals that did not require surgery (p < 0.001, Mann-Whitney-U-test). Using a logistic regression analysis with all variables of the M-ANNHEIM-Severity-Score, we established the M-ANNHEIM-Surgery-Score as a simplified new tool to identify patients that may require surgery. A receiver operating characteristic-analysis revealed a cut-off-value of 9 points within the M-ANNHEIM-Surgery-Score to identify these individuals (sensitivity 78.7 %, specificity 91 %). Based on the M-ANNHEIM-Surgery-Score, we defined three categories for demand of surgery with frequencies of pancreatic operations of 1.6 % (n = 7/440) in the "Baseline-Demand"-category, 7 % (n = 12/172) in the "Low-Demand"-category (p < 0.0001, Chi-square-test, OR 4.6, Confidence Interval (CI) 1.8 - 12), and 54 % (n = 70/129) in the "High-Demand"-category (p < 0.0001, OR 73, CI 32 - 167). Patients that were categorized for the "High-Demand"-category, but were not operated on, had a significantly increased ratio of clinical features that hamper performance of surgery (p < 0.001, Chi-square-test). CONCLUSIONS: The M-ANNHEIM-Surgery-Score represents a useful tool to monitor patients with CP and to estimate the demand of surgery in CP.

Prevalence of inflammatory bowel disease in alcoholic, non-alcoholic and autoimmune pancreatitis.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) frequently reveal features of pancreatic inflammation. However, the prevalence of IBD in patients with alcoholic pancreatitis (AP) and nonalcoholic pancreatitis (NAP) has not yet been determined, and the prevalence of IBD in patients with autoimmune pancreatitis (AiP) from Germany is unknown. AIMS: Thus, we aimed, first, to determine the prevalence of IBD in AP, NAP, and AiP from a tertiary center in Germany and, second, to characterize patients with AiP and IBD. METHODS: We performed a retrospective cross-sectional study to determine the prevalence of IBD in patients with different forms of pancreatitis presenting to our clinic. RESULTS: Compared to the general population and to a control group with viral hepatitis from our clinic, we observed the most significant increase of IBD in patients with AiP (n = 3/28; p < 0.0001 vs. general population, binomial proportion test; p = 0.0112 vs. hepatitis group, Fisher's exact test), followed by a significant increase in subjects with NAP (n = 11/278; p < 0.0001 vs. general population, binomial proportion test; p = 0.0338 vs. hepatitis group, Fisher's exact test). A review of previous studies on the prevalence of IBD among patients with AiP revealed a combined prevalence of 12 % (n = 43/355). Type 2 AiP is significantly more often associated with IBD than type 1 AiP (n = 28/48, 58 % vs. n = 7/129, 5 %; combined patient cohort, p < 10E - 12; Fisher's exact test). CONCLUSIONS: Immune-mediated mechanisms related to IBD may participate in the development of AiP, especially AiP type 2, and may also increase the risk for the development of other forms of pancreatic inflammation.

Prevalence and Incidence of Autoimmune Pancreatitis in the Population Living in the Southwest of Germany.

BACKGROUND/AIMS: The prevalence and incidence of autoimmune pancreatitis (AiP) in those living in western countries are largely unknown. We aimed to determine the prevalence of AiP among patients with pancreatitis presenting to our tertiary referral center in Mannheim, Germany; and to estimate the incidence of AiP in the Southwest of Germany. METHODS: We performed a retrospective cross-sectional analysis and determined the prevalence of AiP in patients with acute pancreatitis (AP) or chronic pancreatitis (CP). Patients (n = 704; alcoholic pancreatitis n = 373, nonalcoholic pancreatitis n = 331) were stratified into the Retrospective-Pancreas-Cohort (RPC, period 1998-2008, n = 534) and the Pancreas-Clinic-Cohort (PCC, periods 2008-2010 and 2013-2014, n = 170, with detailed investigation for features of AiP). Diagnosis of AiP was established by International-Consensus-Diagnostic-Criteria and Unifying-Autoimmune-Pancreatitis-Criteria. RESULTS: In the RPC, the prevalence of AiP was 5.9% (n = 13/221) among individuals with nonalcoholic pancreatitis (n = 1/61 with AP, 1.6%; n = 12/160 with CP, 7.5%). In the PCC, the prevalence of AiP was 9.1% (n = 10/110) among patients with nonalcoholic pancreatitis (n = 2/24 with AP, 8.3%; n = 8/86 with CP, 9.3%), and 1.7% (n = 1/60) among subjects with alcoholic pancreatitis. We estimated the incidence of AiP with 0.29 per 100,000 population each year. CONCLUSION: The prevalence rate of AiP may account for 9% of patients with nonalcoholic pancreatitis but is almost never observed in patients with alcoholic pancreatitis. The incidence of AiP in Germany appears lower than 1 per 100,000 population.

Genetic Variants in the Manganese Superoxide Dismutase 2 Gene and in the Catalase Gene are not Associated With Alcoholic Chronic Pancreatitis.

AIMS: Oxidative stress may contribute to the development of chronic pancreatitis (CP). The enzymes manganese superoxide dismutase 2 (MnSOD, SOD2) and catalase (CAT) counteract free radical activity within the mitochondria and the cytosol. Moreover, CAT activity contributes to the transformation of ethanol to acetaldehyde, a toxic intermediate product of ethanol metabolism, which has been associated with pancreatic damage. Common functional polymorphisms have been described in the MnSOD gene [rs4880, NM_000636.3:c.47 T > C, alanine (ALA) to valine (Val)] and in the CAT promoter region [rs1001179, NG_013339.1:g.4760 C > T]. We investigated whether these polymorphisms are associated with alcoholic CP. METHODS: We genotyped 470 patients with alcoholic CP for these MnSOD and CAT polymorphisms. We also analysed these variants in 357 healthy control subjects, and in an additional control group of 113 individuals with non-alcoholic CP. We used the age at onset of CP as marker of disease severity and investigated whether different genotypes are associated with different ages at onset. In patients with alcoholic CP, we investigated whether an interaction exists between smoking behaviour and genotypes by comparing genotype distributions in smokers and non-smokers. RESULTS: We did not observe significant differences of genotype frequencies between patient groups and controls. In patient groups, we did not find significant differences in the ages at onset between different genotypes. We did not observe an interaction between these polymorphisms. We did not find an association of these variants with smoking behaviour. CONCLUSIONS: The investigated MnSOD and CAT polymorphisms do not predispose to the development of alcoholic CP. SHORT SUMMARY: Patients with alcoholic pancreatitis and controls were genotyped for polymorphisms in oxidative stress genes. There were no significant differences of genotype frequencies between patients and controls, and no association with the age at onset of disease was observed. The polymorphisms are not associated with the development of alcoholic pancreatitis.

Diagnosing autoimmune pancreatitis with the Unifying-Autoimmune-Pancreatitis-Criteria.

BACKGROUND/OBJECTIVES: We had developed the Unifying-Autoimmune-Pancreatitis-Criteria (U-AIP) to diagnose autoimmune pancreatitis (AiP) within the M-ANNHEIM classification of chronic pancreatitis. In 2011, International-Consensus-Diagnostic-Criteria (ICDC) to diagnose AiP have been published. We had applied the U-AIP long before the ICDC were available. The aims of the study were, first, to describe patients with AiP diagnosed by the U-AIP; second, to compare diagnostic accuracies of the U-AIP and other diagnostic systems; third, to evaluate the clinical applicability of the U-AIP. METHODS: From 1998 until 2008, we identified patients with AiP using U-AIP, Japanese-, Korean-, Asian-, Mayo-HISORt-, Revised-Mayo-HISORt- and Italian-criteria. We retrospectively verified the diagnosis by ICDC and Revised-Japanese-2011-criteria, compared diagnostic accuracies of all systems and evaluated all criteria in consecutive patients with pancreatitis (2009 until 2010, Pancreas-Outpatient-Clinic-Cohort, n = 84). We retrospectively validated our diagnostic approach in consecutive patients with a pancreatic lesion requiring surgery (Surgical-Cohort, n = 98). RESULTS: Overall, we identified 21 patients with AiP. Unifying-Autoimmune-Pancreatitis-Criteria and ICDC presented the highest diagnostic accuracies (each 98.8%), highest Youden indices (each 0.95238), and highest proportions of diagnosed patients (each n = 20/21, U-AIP/ICDC vs. other diagnostic systems, p < 0.05, McNemar test). In the Pancreas-Outpatient-Clinic-Cohort, seven patients were diagnosed with AiP (n = 6 by U-AIP, n = 1 by Asian-criteria). International-Consensus-Diagnostic-Criteria confirmed the diagnosis in these individuals. Based on partial fulfillment of U-AIP, AiP was initially suspected in 13% (n = 10/77) of remaining patients from the Pancreas-Outpatient-Clinic-Cohort. In the Surgical-cohort, we identified one patient with AiP by U-AIP and ICDC. CONCLUSIONS: Unifying-Autoimmune-Pancreatitis-Criteria revealed a satisfactory clinical applicability and offered an additional approach to diagnose AiP.

Risk of Cancer in Patients with Autoimmune Pancreatitis: A Single-Center Experience from Germany.

BACKGROUND/AIMS: Autoimmune pancreatitis (AIP) has been associated with an increased risk of malignant diseases. We aimed to describe the incidence of malignant diseases in patients with AIP compared to the general population and to characterize the clinical presentation of these patients. METHODS: We retrospectively analyzed data from 28 patients with AIP presenting to the clinic (periods 1998 until 2010, 2012 until September 2015). We retrieved the expected cancer incidence of the general population from the German cancer registry. We determined the ratio of patients with malignant disease, characterized the clinical presentation of these patients, and calculated standardized incidence ratios (SIR). RESULTS: We observed 6 malignant diseases in 5 patients with AIP (non-Hodgkin lymphoma, colon cancer, breast cancer and ovarian carcinoma, breast cancer, bladder cancer, n = 5/28, 17.9%) during an overall observation period of 223 person-years (2,675 months). The overall SIR of cancer in patients with AIP was 17.3 (95% CI 5.9-35.8), and the overall incidence rate of malignant diseases in these patients was significantly increased compared to the expected incidence in the German population (Fisher's exact test, p < 0.001). CONCLUSION: The incidence of malignant diseases in patients with AIP is significantly increased compared to the general population. Careful clinical monitoring is required in individuals with AIP to exclude the occurrence of malignancy.

Management of diverticular disease.

Diverticular disease is a common condition in Western countries and the incidence and prevalence of the disease is increasing. The pathogenetic factors involved include structural changes in the gut that increase with age, a diet low in fibre and rich in meat, changes in intestinal motility, the concept of enteric neuropathy and an underlying genetic background. Current treatment strategies are hampered by insufficient options to stratify patients according to individual risk. One of the main reasons is the lack of an all-encompassing classification system of diverticular disease. In response, the German Society for Gastroenterology and Digestive Diseases (DGVS) has proposed a classification system as part of its new guideline for the diagnosis and management of diverticular disease. The classification system includes five main types of disease: asymptomatic diverticulosis, acute uncomplicated and complicated diverticulitis, as well as chronic diverticular disease and diverticular bleeding. Here, we review prevention and treatment strategies stratified by these five main types of disease, from prevention of the first attack of diverticulitis to the management of chronic complications and diverticular bleeding.

The effect of body weight on the severity and clinical course of ulcerative colitis.

PURPOSE: Obesity is a risk factor for inflammatory diseases such as nonalcoholic steatohepatitis, pancreatitis, and Crohn's disease. The effect of being overweight or obese on the severity and clinical course of ulcerative colitis (UC) was assessed in a retrospective analysis of data from 2000-2006. METHODS: Two hundred and two consecutive UC patients were categorized according to body mass index (BMI). Patient and disease characteristics were compared between BMI categories using chi-square or Kruskal-Wallis tests. The percentage of patients with active UC, complications, steroid therapy, or immunosuppressive therapy was calculated for each group, and matched pair analyses were performed. RESULTS: Ten patients (5%) were underweight, 111 (55%) were normal weight, 54 (26.7%) were overweight, and 27 (13.4%) were obese. Pancolitis was inversely related to weight. BMI was also inversely correlated to disease severity, with a significantly smaller proportion of years with chronic active disease among overweight subjects versus normal-weight subjects (17.6 versus 23.9%, p = 0.05). More overweight than normal-weight patients had no chronic active disease in any year (66 versus 49%, p = 0.06), and the proportion of years with disease complications was higher in normal weight than in overweight subjects (1.8 versus 0.4%, p = 0.08). Disease activity during 2000-2006 was higher for underweight versus normal-weight patients, and only 20% of underweight subjects had no hospital admission compared to 80% of normal-weight patients (p = 0.07). CONCLUSIONS: This first study to explore the influence of obesity on UC showed that high BMI had rather a favorable effect on the prognosis, whereas low BMI pointed to a more severe course of the disease.

Rapid progression of a splenic aneurysm due to segmental arterial mediolysis: a rare cause of acute pancreatitis.

BACKGROUND: The etiology of acute pancreatitis can be manifold, beside the usual causes. We are reporting an unusual cause that triggered acute pancreatitis. PATIENT & RESULTS: A 50 year-old male experienced attacks of acute pancreatitis (abdominal pain and elevated amylase and lipase) during sexual arousal. Serial imaging showed a rapidly-progressing, partly-thrombosed splenic artery aneurysm, with local compression of the pancreas. After angiographic coiling, the attacks subsided. Further angiography revealed additional aneurysms consistent with segmental arterial mediolysis at other sites of the body. Molecular analysis regarding Ehlers-Danlos-syndrome and genetic factors for pancreatitis, autoantibodies and Syphilis serology was negative. CONCLUSIONS: Acute pancreatitis was triggered by a transient rise in blood pressure during sexual stimulation, which caused rapid progression of a splenic artery aneurysm as part of systemic segmental arterial mediolysis.

Variants in CPA1 are strongly associated with early onset chronic pancreatitis.

Chronic pancreatitis is an inflammatory disorder of the pancreas. We analyzed CPA1, encoding carboxypeptidase A1, in subjects with nonalcoholic chronic pancreatitis (cases) and controls in a German discovery set and three replication sets. Functionally impaired variants were present in 29/944 (3.1%) German cases and 5/3,938 (0.1%) controls (odds ratio (OR) = 24.9, P = 1.5 × 10(-16)). The association was strongest in subjects aged ≤ 10 years (9.7%; OR = 84.0, P = 4.1 × 10(-24)). In the replication sets, defective CPA1 variants were present in 8/600 (1.3%) cases and 9/2,432 (0.4%) controls from Europe (P = 0.01), 5/230 (2.2%) cases and 0/264 controls from India (P = 0.02) and 5/247 (2.0%) cases and 0/341 controls from Japan (P = 0.013). The mechanism by which CPA1 variants confer increased pancreatitis risk may involve misfolding-induced endoplasmic reticulum stress rather than elevated trypsin activity, as is seen with other genetic risk factors for this disease.

The effect of third-party reporting on adoption of evidence-based mesalazine regimens in ulcerative colitis: an observational study.

BACKGROUND AND AIMS: The optimal mesalazine dosing strategy for ulcerative colitis (UC) continues to evolve. The current study aimed to explore whether documenting drug use could prompt changes in prescribing habits. METHODS: In a multicenter, prospective, observational study, outpatients with active or quiescent UC were enrolled if they were receiving, or were planned to receive, sustained release mesalazine microgranules (Pentasa). Clinical and prescribing data were collected at study entry, after 2 and 8 weeks. Physician-reported influences on prescribing decisions were recorded at study entry. RESULTS: 360 patients were analyzed (203 active UC, 157 remission). Prior to study entry, the range of oral mesalazine doses was 0.50-6.00 g/day in active UC patients, and 0.50-4.00 g/day for patients in remission. These changed to 1.50-5.00 g/day and 1.00-4.00 g/day, respectively, at study entry with little change thereafter. Use of a single daily mesalazine dose increased from 16.7% to 58.0% of active cases during the study, and from 5.9% to 46.8% in remission cases. Gastroenterologists reported that their basis for prescription decision-making was most frequently medical experience (80.8%), followed by guidelines (67.2%), further education or colleagues' recommendations (50.0%) and current study results (20.0%). CONCLUSION: In this analysis of mesalazine dosing in routine clinical practice, there was an improvement in adherence to European Crohn's and Colitis Organisation (ECCO) guidelines and in use of once-daily dosing, consistent with recent trial results, following documentation of dosing regimens. Written reporting of drug dosing schedules should be considered fundamental for chronic, complex diseases such as UC.

Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens.

CFTR mutations enhance susceptibility for idiopathic chronic pancreatitis (ICP) and congenital bilateral absence of the vas deferens (CBAVD); however, it is unknown why CFTR heterozygotes are at increased disease risk. We recently showed that common CFTR variants are associated with aberrantly spliced transcripts. Here, we genotyped for common CFTR variants and tested for associations in two ICP (ICP-A: 126 patients, 319 controls; ICP-B: 666 patients, 1,181 controls) and a CBAVD population (305 patients, 319 controls). Haplotype H10 (TG11-T7-470V) conferred protection (ICP-A: OR 0.19, P<0.0001; ICP-B: OR 0.78, P = 0.06; CBAVD OR 0.08, P<0.001), whereas haplotype H3 (TG10-T7-470M) increased disease risk (ICP-A: OR 8.34, P = 0.003; ICP-B: OR 1.88, P = 0.007; CBAVD: OR 5.67, P = 0.01). The risk of heterozygous CFTR mutations carriers for ICP (OR 2.44, P<0.001) and CBAVD (OR 14.73, P<0.001) was fully abrogated by the H10/H10 genotype. Similarly, ICP risk of heterozygous p.Asn34Ser SPINK1 mutation carriers (OR 10.34, P<0.001) was compensated by H10/H10. Thus, common CFTR haplotypes modulate ICP and CBAVD susceptibility alone and in heterozygous CFTR and p.Asn34Ser mutation carriers. Determination of these haplotypes helps to stratify carriers into high- and low-risk subjects, providing helpful information for genetic counseling.

Complete analysis of the human mesotrypsinogen gene (PRSS3) in patients with chronic pancreatitis.

BACKGROUND/AIMS: A sustained imbalance of pancreatic proteases and their inhibitors seems to be important for the development of chronic pancreatitis (CP). Mesotrypsin (PRSS3) can degrade intrapancreatic trypsin inhibitors that protect against CP. Genetic variants that cause higher mesotrypsin activity might increase the risk for CP. METHODS: We analyzed all 5 exons and the adjacent non-coding sequences of PRSS3 by direct sequencing of 313 CP patients and 327 controls. Additionally, exon 4 was investigated in 855 patients and 1,294 controls and a c.454+191G>A variant in 855 patients and 1,467 controls. The c.499A>G (p.T167A) variant was analyzed functionally using transiently transfected HEK 293T cells. RESULTS: In the exonic regions, the previously described common c.94_96delGAG (p.E32del) variant and a novel p.T167A non-synonymous alteration were identified. Extended analysis of the p.T167A variant revealed no association to CP and in functional assays p.T167A showed normal secretion and activity. Variants of the intronic regions, including the extensively analyzed c.454+191G>A alteration, were not associated with the disease. Haplotype reconstruction using variants with a minor allele frequency of >1% revealed no CP-associated haplotype. CONCLUSIONS: Although the trypsin inhibitor-degrading activity qualified PRSS3 as a candidate for a novel CP susceptibility gene, we found no association between a specific variant or haplotype and CP in our cohort with a high suspicion of genetically determined disease.

Investigation of the SPINK1 N34S mutation in Romanian patients with alcoholic chronic pancreatitis. A clinical analysis based on the criteria of the M-ANNHEIM classification.

BACKGROUND AND AIMS: The N34S mutation in the serine protease inhibitor Kazal type I (SPINK1) gene has been associated with chronic pancreatitis. Clinical data about the phenotypic expression of alcoholic chronic pancreatitis with the N34S variant are limited. The prevalence of the N34S mutation in patients with chronic pancreatitis and healthy individuals from Eastern Europe is unknown. METHODS: We studied Romanian patients with chronic pancreatitis and investigated the clinical presentation in patients with N34S mutation. The SPINK1 N34S variant was analysed in 94 chronic pancreatitis patients and 96 healthy controls by an allele specific PCR method and a restriction fragment length polymorphism method. A meta-analysis was conducted with previous N34S association studies. The clinical course of alcoholic pancreatitis was evaluated according to the severity criteria of the M-ANNHEIM classification system of chronic pancreatitis. RESULTS: A heterozygous N34S mutation was found in 1 of 96 healthy individuals (1%) and in 4 of 80 patients (5%) with alcoholic chronic pancreatitis. The meta-analysis confirmed the status of N34S as a risk factor for the development of alcoholic chronic pancreatitis (OR=5.3). However, the clinical course of the disease was similar in patients with and without N34S mutation. CONCLUSION: The N34S mutation is a weak risk factor for alcoholic chronic pancreatitis.

The role of epoxide hydrolase Y113H gene variant in pancreatic diseases.

OBJECTIVES: Chronic pancreatitis (CP) and pancreatic adenocarcinoma (pCA) are associated with risk factors such as alcohol intake and tobacco smoking. Microsomal epoxide hydrolase (EPHX1) is a phase II detoxifying enzyme capable of tobacco-borne toxicant inactivation. We studied the role of the EPHX1 c.337T>C (p.Y113H) variant, whichleads to altered enzyme activity, in pancreatic diseases. METHODS: We genotyped 2391 patients by melting curve analysis. We enrolled 367 patients with pCA, 341 patients with alcoholic CP (aCP), 431 patients with idiopathic CP or hereditary pancreatitis, 192 patients with acute pancreatitis, and 679 controls of German descent. We replicated data in 77 patients with aCP and 304 controls from The Netherlands. RESULTS: In German patients with aCP, Y113 was more common than in controls (allele frequencies, 0.73 vs 0.68; risk ratio, 1.21 [95% confidence interval, 1.05-1.39]). However, we could not confirm this association in the Dutch population (allele frequencies, 0.62 vs 0.68, P=not significant). In total, Y113 frequency was 0.71 in aCP and 0.68 in controls (P = not significant). Allele frequencies did not differ in the other disease groups (acute pancreatitis, 0.69; idiopathic CP or hereditary pancreatitis, 0.68; pCA, 0.68; and control, 0.68). CONCLUSIONS: The EPHX1 Y113H variant is not associated with pancreatic diseases indicating that EPHX1 does not play a significant role in the initiation of pancreatic inflammation or cancer.

Angiotensin-converting enzyme insertion/deletion polymorphism in patients with acute and chronic pancreatitis.

BACKGROUND: Reduction in angiotensin-converting enzyme (ACE) activity has been shown to attenuate pancreatic stellate cell activation and pancreatic fibrosis and suggested as a potential treatment for chronic pancreatitis. The ACE gene insertion/deletion (I/D) polymorphism in intron 16 accounts for nearly half the variation in serum ACE levels. This study determined the frequency of the I/D polymorphism in patients with acute and chronic pancreatitis. METHODS: In total, 887 patients (346 with alcoholic, 443 with nonalcoholic, and 98 with acute pancreatitis) were enrolled, and were compared with 1294 healthy controls. Genotyping of the I/D polymorphism was performed by PCR or melting curve analyses. RESULTS: No significant differences were found in the prevalence of the ACE-deletion genotype frequencies when patients with alcoholic (27.5%), nonalcoholic (26.4%), and acute pancreatitis (32.7%) were compared with controls (26.9%). Likewise, allele frequencies of the ACE deletion polymorphism were not significantly different in patients with alcoholic (53.8%), nonalcoholic (50.6%), and acute pancreatitis (54.1%) and controls (52.7%). CONCLUSION: The I/D polymorphism of the ACE gene was not found to be associated with acute and chronic pancreatitis.

Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis.

Chronic pancreatitis is a persistent inflammatory disease of the pancreas, in which the digestive protease trypsin has a fundamental pathogenetic role. Here we have analyzed the gene encoding the trypsin-degrading enzyme chymotrypsin C (CTRC) in German subjects with idiopathic or hereditary chronic pancreatitis. Two alterations in this gene, p.R254W and p.K247_R254del, were significantly overrepresented in the pancreatitis group, being present in 30 of 901 (3.3%) affected individuals but only 21 of 2,804 (0.7%) controls (odds ratio (OR) = 4.6; confidence interval (CI) = 2.6-8.0; P = 1.3 x 10(-7)). A replication study identified these two variants in 10 of 348 (2.9%) individuals with alcoholic chronic pancreatitis but only 3 of 432 (0.7%) subjects with alcoholic liver disease (OR = 4.2; CI = 1.2-15.5; P = 0.02). CTRC variants were also found in 10 of 71 (14.1%) Indian subjects with tropical pancreatitis but only 1 of 84 (1.2%) healthy controls (OR = 13.6; CI = 1.7-109.2; P = 0.0028). Functional analysis of the CTRC variants showed impaired activity and/or reduced secretion. The results indicate that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity.

HFE genotypes in patients with chronic pancreatitis and pancreatic adenocarcinoma.

PURPOSE: The homozygous p.C282Y variant of the HFE gene is a major risk factor for hereditary hemochromatosis, a disorder of iron metabolism resulting in progressive iron accumulation in a variety of organs including the pancreas. Heterozygosity of p.C282Y and p.H63D may increase susceptibility to chronic liver and pancreatic disease. This study determines the frequencies of p.C282Y and p.H63D alterations in patients with chronic pancreatitis and pancreatic adenocarcinoma. METHODS: In total, 958 patients (349 with alcoholic pancreatitis, 343 with idiopathic pancreatitis, 64 with familial chronic pancreatitis, 34 with acute pancreatitis, and 168 with pancreatic adenocarcinoma) were enrolled and compared with 681 healthy and 100 alcoholic controls. Furthermore, 45 parent-offspring trios were included for segregation analysis. Genotyping of p.C282Y and p.H63D was performed by restriction fragment length polymorphism or melting curve analyses. RESULTS: No significant differences were found in heterozygosity for p.C282Y and p.H63D when patients with alcoholic (8.0/21.5%), idiopathic (7.3/24.5%), or familial (9.8/23.0%) pancreatitis, or pancreatic adenocarcinoma (5.4/28.6%) were compared with healthy (6.2/24.8%) and alcoholic (7.0/25.0%) controls. Neither genotype was associated with the presence of secondary diabetes mellitus in patients with chronic pancreatitis. CONCLUSION: Although hemochromatosis is associated with pancreatic pathology, the p.C282Y and p.H63D variants do not play a significant role in the pathogenesis of chronic pancreatitis or pancreatic adenocarcinoma.