Do CTRC mutations affect the development of alcoholic chronic pancreatitis and its course among Poles: Preliminary study.

BACKGROUND: Genetic mutations are one of the etiological factors that predispose people to develop chronic pancreatitis. OBJECTIVES: The aim of our study was to examine the effect of p.Trp55*, p.Arg254Trp and c.738_761del mutations in the chemotrypsin gene (CTRC) on the development of alcoholic chronic pancreatitis (ACP) in order to answer the questions whether these mutations vary between gender groups, whether they were related to the age when ACP was first diagnosed, and whether they affected the morphological changes in the pancreas and the course of ACP. MATERIAL AND METHODS: The study included 124 patients with ACP, 52 with nonalcoholic pancreatitis and 52 controls. The p.Trp55*, c.738_761del and p.Arg254Trp mutations in the CTRC gene were tested by the polymerase chain reaction (PCR). RESULTS: The c.738_761del and p.Arg254Trp mutations occurred in 3.07% and 1.31% of cases, respectively. None of the examined patients were found to have the p.Trp55* mutation. The frequency of detected mutations did not significantly differ between the study groups. The c.738_761del mutation was detected more frequently in women than in men. No significant differences were found in the age at ACP onset, morphological changes affecting the pancreas, or in the course of ACP between the patients with and without the 2 examined mutations. The c.738_761del mutation was significantly more frequent in the diabetic patients than in the non-diabetics. The patients with this mutation more frequently required surgery than those without the c.738_761del mutation. CONCLUSIONS: No relationship between the c.738_761del and p.Arg254Trp mutations and the development of APC was found. The c.738_761del mutation was more frequent in females than in males. Neither mutation affected the patient's age at ACP onset or its course. In contrast to p.Arg254Trp, the c.738_761del mutation correlated with diabetes development and the need for surgery in the course of ACP.

Racial Differences in the Clinical Profile, Causes, and Outcome of Chronic Pancreatitis.

OBJECTIVES: Racial differences in susceptibility and progression of pancreatitis have been reported in epidemiologic studies using administrative or retrospective data. There has been little study, however, on the clinical profile, causes, and outcome of chronic pancreatitis (CP) in black patients. METHODS: We analyzed data on black patients with CP prospectively enrolled in the multicenter North American Pancreatitis Studies from 26 US centers during the years 2000-2014. CP was defined by definitive evidence on imaging studies or histology. Information on demographics, etiology, risk factors, disease phenotype, treatment, and perceived effectiveness was obtained from responses to detailed questionnaires completed by both patients and physicians. RESULTS: Of the 1,159 patients enrolled, 248 (21%) were black. When compared with whites, blacks were significantly more likely to be male (60.9 vs. 53%), ever (88.2 vs. 71.8%), or current smokers (64.2 vs. 45.9%), or have a physician-defined alcohol etiology (77 vs. 41.9%). There was no overall difference in the duration of CP although for alcoholic CP, blacks had a longer duration of disease (8.6 vs. 6.97 years; P=0.02). Blacks were also significantly more likely to have advanced changes on pancreatic morphology (calcifications (63.3 vs. 55.2%), atrophy (43.2 vs. 34.6%), pancreatic ductal stricture or dilatation (72.6 vs. 65.5%) or common bile duct stricture (18.6 vs. 8.2%)) and function (endocrine insufficiency 39.9 vs. 30.2%). Moreover, the prevalence of any (94.7 vs. 83%), constant (62.6 vs. 51%), and severe (78.4 vs. 65.8%) pain and disability (35.1 vs. 21.4%) were significantly higher in blacks. Observed differences were in part related to variances in etiology and duration of disease. No differences in medical or endoscopic treatments were seen between races although prior cholecystectomy (31.1 vs. 19%) was more common in white patients. CONCLUSIONS: Differences were observed between blacks and whites in the underlying cause, morphologic expression, and pain characteristics of CP, which in part are explained by the underlying risk factor(s) with alcohol and tobacco being much more frequent in black patients as well as disease duration.

Genetic polymorphisms in alcohol dehydrogenase, aldehyde dehydrogenase and alcoholic chronic pancreatitis susceptibility: a meta-analysis.

PURPOSE: This study was aimed to determine the relationship of alcohol-metabolizing enzymes ADH2, ADH3, and ALDH2 polymorphisms with the susceptibility to alcoholic chronic pancreatitis (ACP). METHODS: Meta-analyses that evaluated the association of ADH2, ADH3, and ALDH2 variations with ACP were performed. RESULTS: Eight case-control studies were selected for analysis. The overall data revealed a significant association of ADH2 polymorphism (OR=1.56, 95% CI=1.42-1.72, P=0.000 for dominant model; OR=1.63, 95% CI=1.55-1.71, P=0.000 for homozygote comparison model; OR=1.11, 95% CI=1.01-1.22, P=0.030 for allelic contrast model), ADH3 polymorphism (OR=0.95, 95% CI=0.86-1.06, P=0.389 for dominant; OR=0.64, 95% CI=0.44-0.93, P=0.020 for homozygote comparison; and OR=0.87, 95% CI=0.77-0.99, P=0.039 for allelic contrast model) and ALDH2 polymorphism (OR=0.57, 95% CI=0.40-0.81, P=0.002 for dominant; OR=0.50, 95% CI=0.23-1.08, P=0.079 for homozygote comparison; and OR=0.58, 95% CI=0.41-0.84, P=0.003 for allelic contrast model) with ACP risk. The subgroup analyses suggested that the variant ADH2*2/*2+*1/*2, ADH2*2/*2 genotype and ADH2*2 allele significantly increased ACP risk among Asian individuals; the variant ADH3*2/*2 genotype and ADH3*2 allele significantly decreased ACP risk among non-Asian individuals; and the variant ALDH2*2/*2+*1/*2 genotype and ALDH2*2 allele significantly decreased ACP risk among Asians. CONCLUSIONS: ADH2, ADH3 and ALDH2 polymorphisms may be susceptibility facts of ACP, and it may be ethnic and race-dependent.

Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis.

BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) gene, responsible for the development of cystic fibrosis, is known as a pancreatitis susceptibility gene. Direct DNA sequencing of PCR-amplified CFTR gene segments is a first-line method to detect unknown mutations, but it is a tedious and labor-intensive endeavor given the large size of the gene (27 exons, 1,480 amino acids). Next-generation sequencing (NGS) is becoming standardized, reducing the cost of DNA sequencing, and enabling the generation of millions of reads per run. We here report a comprehensive analysis of CFTR variants in Japanese patients with chronic pancreatitis using NGS coupling with target capture. METHODS: Exon sequences of the CFTR gene from 193 patients with chronic pancreatitis (121 idiopathic, 46 alcoholic, 17 hereditary, and nine familial) were captured by HaloPlex target enrichment technology, followed by NGS. RESULTS: The sequencing data covered 91.6 % of the coding regions of the CFTR gene by ≥ 20 reads with a mean read depth of 449. We could identify 12 non-synonymous variants including three novel ones [c.A1231G (p.K411E), c.1753G>T (p.E585X) and c.2869delC (p.L957fs)] and seven synonymous variants including three novel ones in the exonic regions. The frequencies of the c.4056G>C (p.Q1352H) and the c.3468G>T (p.L1156F) variants were higher in patients with chronic pancreatitis than those in controls. CONCLUSIONS: Target sequence capture combined with NGS is an effective method for the analysis of pancreatitis susceptibility genes.

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 incidence and case-fatality rates of acute biliary, alcoholic, and idiopathic pancreatitis in California, 1994-2001.

OBJECTIVE: To better define the epidemiology of acute pancreatitis in a racially diverse population. METHODS: Analysis of all patients hospitalized in California with first-time acute pancreatitis for the period between January 1994 and September 2001. Subtypes were classified based on the presence or absence of predisposing conditions. RESULTS: There were 70,231 patients hospitalized for first-time acute pancreatitis; 32.6% had biliary tract disease alone, 20.3% had alcohol abuse alone, and 36.6% were idiopathic. The age-standardized incidence increased by 32% from 33.2 to 43.8 cases per 100,000 adults for the period between 1994 and 2001, with the largest increase in the biliary group (52%). The standardized incidence rate of alcoholic and idiopathic pancreatitis was highest in African Americans, whereas biliary pancreatitis was highest in Hispanics. There was no change over time in the percentage of patients dying in the first 14 or 91 days; and in a risk-adjusted model, patients with alcoholic pancreatitis had the highest risk of dying. CONCLUSIONS: The incidence rate of acute pancreatitis rose for the period between 1994 and 2001. However, there was no reduction in the 14- or 91-day case-fatality rate. Further research is needed to explain both the rise in the incidence rate of pancreatitis and the absence of any improvement in the early case-fatality rate.

Extrapancreatic manifestations of acute pancreatitis in African-American and Hispanic patients.

OBJECTIVE: Many studies have been published on acute pancreatitis but few, if any, on extrapancreatic manifestations (EPM) in African Americans and Hispanics. We studied the effect of EPM on mortality in these 2 ethnic groups. METHODS: Records of 760 acute pancreatitis patients (417 African-American and 343 Hispanic), ages 19-85 years, over a 15-year period were reviewed retrospectively. Data were analyzed for EPM and mortality. RESULTS: Of the 760 patients, alcohol use was identified as the etiology in 53% of cases and gallstones in 42%. EPM were present in 148 patients (19.5%). Gastrointestinal bleeding (22%) was the most common EPM. Patients with EPM did not differ from patients without EPM on demographics or acute pancreatitis-related variables (P > 0.05). Patients with EPM had higher odds of having comorbidity relative to patients without EPM (OR = 2.9, CI = 2.0-4.2). Of 760 patients, 109 died (14%). However, mortality was significantly higher (26%) in patients with EPM in comparison to those without EPM (11%), P = 0.001. Controlling for other variables, patients with EPM had higher odds of mortality relative to patients without EPM (OR = 2.8, CI = 1.7-4.4). CONCLUSION: Mortality was high in our patients compared with the literature (5%-10%). EPM increased the mortality significantly (26%).

Racial factors and the risk of chronic pancreatitis.

OBJECTIVE: It is unclear why some alcohol abusers develop alcoholic cirrhosis whereas others contract chronic pancreatitis. The aim of this study was to examine the importance of race as a risk factor for the development of chronic pancreatitis. METHODS: We compared the racial status of 1883 patients discharged with a first-listed diagnosis of two diseases strongly related to alcohol abuse: 433 patients with chronic pancreatitis (ICD 5771) and 1450 patients with alcoholic cirrhosis (ICD 5712). Information came from discharge statistics maintained by two acute care hospitals in New York City and one acute care hospital in Lisbon, Portugal. The study period included the years 1989-1996 in the US and 1989-1994 in Portugal. RESULTS: A total of 215 (50%) of the 433 chronic pancreatitis patients were black compared with 333 (23%) of the 1450 patients with alcoholic cirrhosis. When adjusted for sex and hospital site, patients with pancreatitis were significantly more likely to be black than patients with cirrhosis (odds ratio 2.5, 95% confidence interval 1.9-3.2, p < 0.001). CONCLUSIONS: In comparison with white patients, black patients are two to three times more likely to be hospitalized for chronic pancreatitis than alcoholic cirrhosis. This highly significant (p < 0.001) difference was observed in both men and women: in three different hospitals, and in two different countries. The explanation is unknown, but could be related to racial differences in diet, type or quantity of alcohol consumption, smoking, or ability to detoxify substances harmful to the liver or pancreas.