Mary E. Money

Alcohol and Smoking as Risk Factors in an Epidemiology Study of Patients With Chronic Pancreatitis

BACKGROUND & AIMS Alcohol has been implicated in the development of chronic pancreatitis (CP) in 60%-90% of patients, although percentages in the United States are unknown. We investigated the epidemiology of alcohol-related CP at tertiary US referral centers. METHODS We studied data from CP patients (n = 539) and controls (n = 695) enrolled in the North American Pancreatitis Study-2 from 2000 to 2006 at 20 US referral centers. CP was defined by definitive evidence from imaging or histologic analyses. Subjects and physicians each completed a study questionnaire. Using physician-assigned diagnoses, patients were assigned to an etiology group: alcohol (with/without other diagnoses), nonalcohol (any etiology of CP from other than alcohol), or idiopathic (no etiology identified). RESULTS The distribution of patients among etiology groups was: alcohol (44.5%), nonalcohol (26.9%), and idiopathic (28.6%). Physicians identified alcohol as the etiology more frequently in men (59.4% men vs 28.1% women), but nonalcohol (18% men vs 36.7% women) and idiopathic etiologies (22.6% men vs 35.2% women) more often in women (P < .01 for all comparisons). Nonalcohol etiologies were equally divided among obstructive, genetic, and other causes. Compared with controls, patients with idiopathic CP were more likely to have ever smoked (58.6% vs 49.7%, P < .05) or have a history of chronic renal disease or failure (5.2% vs 1.2%, P < .01). In multivariate analyses, smoking (ever, current, and amount) was independently associated with idiopathic CP. CONCLUSIONS The frequency of alcohol-related CP at tertiary US referral centers is lower than expected. Idiopathic CP and nonalcohol etiologies represent a large subgroup, particularly among women. Smoking is an independent risk factor for idiopathic CP.

Combined Bicarbonate Conductance-Impairing Variants in CFTR and SPINK1 Variants Are Associated With Chronic Pancreatitis in Patients Without Cystic Fibrosis

BACKGROUND & AIMS Idiopathic chronic pancreatitis (ICP) is a complex inflammatory disorder associated with multiple genetic and environmental factors. In individuals without cystic fibrosis (CF), variants of CFTR that inhibit bicarbonate conductance but maintain chloride conductance might selectively impair secretion of pancreatic juice, leading to trypsin activation and pancreatitis. We investigated whether sequence variants in the gene encoding the pancreatic secretory trypsin inhibitor SPINK1 further increase the risk of pancreatitis in these patients. METHODS We screened patients and controls for variants in SPINK1 associated with risk of chronic pancreatitis and in all 27 exons of CFTR. The final study group included 53 patients with sporadic ICP, 27 probands with familial ICP, 150 unrelated controls, 375 additional controls for limited genotyping. CFTR wild-type and p.R75Q were cloned and expressed in HEK293 cells, and relative conductances of HCO(3)(-) and Cl(-) were measured. RESULTS SPINK1 variants were identified in 36% of subjects and 3% of controls (odds ratio [OR], 18.1). One variant of CFTR not associated with CF, p.R75Q, was found in 16% of subjects and 5.3% of controls (OR, 3.4). Coinheritance of CFTR p.R75Q and SPINK1 variants occurred in 8.75% of patients and 0.38% of controls (OR, 25.1). Patch-clamp recordings of cells that expressed CFTR p.R75Q showed normal chloride currents but significantly reduced bicarbonate currents (P = .0001). CONCLUSIONS The CFTR variant p.R75Q causes a selective defect in bicarbonate conductance and increases risk of pancreatitis. Coinheritance of p.R75Q or CF causing CFTR variants with SPINK1 variants significantly increases the risk of ICP.

Physical and mental quality of life in chronic pancreatitis: a case-control study from the North American Pancreatitis Study 2 cohort.

Objectives The objective of this study was to define the quality of life (QOL) in patients with chronic pancreatitis (CP). Methods We studied 443 well-phenotyped CP subjects and 611 control subjects prospectively enrolled from 20 US centers between 2000 and 2006 in the North American Pancreatitis Study 2. Responses to the SF-12 questionnaire were used to calculate the mental (MCS) and physical component summary scores (PCS) with norm-based scoring (normal ≥50). Quality of life in CP subjects was compared with control subjects after controlling for demographic factors, drinking history, smoking, and medical conditions. Quality of life in CP was also compared with known scores for several chronic conditions. Results Both PCS (38 [SD, 11.5] vs 52 [SD, 9.4]) and MCS (44 [SD, 11.5] vs 51 [SD, 9.2]) were significantly lower in CP compared with control subjects (P < 0.001). On multivariable analyses, compared with control subjects, a profound decrease in physical QOL (PCS 12.02 points lower) and a clinically significant decrease in mental QOL (MCS 4.24 points lower) was seen due to CP. Quality of life in CP was similar to (heart, kidney, liver, lung disease) or worse than (nonskin cancers, diabetes mellitus, hypertension, rheumatoid arthritis) other chronic conditions. Conclusions The impact of CP on QOL appears substantial. The QOL in CP subjects appears to be worse or similar to the QOL of many other chronic conditions.

Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome

Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase–isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase–isomaltase (SI) gene variants for their potential relevance in IBS. Design We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. Results CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case–control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). Conclusions SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.

Keratin 8 Mutations Are Not Associated with Familial, Sporadic and Alcoholic Pancreatitis in a Population from the United States

Background and Aims: Genetic predispositions play a major role in the development of chronic pancreatitis. Recently, a mutation in the keratin 8 gene (G62C) was reported to be associated with chronic pancreatitis in Italy. We determined whether mutations in the keratin 8 gene are associated with familial, sporadic and alcoholic recurrent acute or chronic pancreatitis in a population from the United States. Methods: We investigated the relevant genomic region of the keratin 8 gene in 80 patients with familial pancreatitis without a cationic trypsinogen (PRSS1) gene mutation from 52 different families, 21 patients with familial hereditary pancreatitis and a PRSS1 mutation from 20 different families, 126 patients with sporadic pancreatitis without a PRSS1 mutation, 61 patients with alcoholic pancreatitis and 271 controls by direct DNA sequencing. Results: We found the heterozygous G62C mutation in n = 3/80 patients (n = 2/52 patients from different families, 3.8%) with familial pancreatitis without PRSS1 mutation and in n = 3/126 patients (2.4%) with sporadic pancreatitis. We detected an adjacent heterozygous I63V mutation in n = 2/80 patients (n = 2/52 patients from different families, 3.8%) with familial pancreatitis without PRSS1 mutation and in n = 1/61 patients (1.6%) with alcoholic pancreatitis. We found the G62C mutation in n = 2/271 controls (0.7%) and the I63V mutation in n = 2/271 controls (0.7%). There were no statistically significant differences in the genotype frequencies between patients and controls (p > 0.05). Screening of additional available family members revealed that these variants did not segregate with the disease phenotype. There was no statistically significant difference in the frequency of these keratin 8 variants between patients with chronic pancreatitis and controls (p > 0.05). Conclusion: These keratin 8 variants are not associated with familial, sporadic or alcoholic pancreatitis.

Pilot study: a randomised, double blind, placebo controlled trial of pancrealipase for the treatment of postprandial irritable bowel syndrome-diarrhoea

Objective To evaluate the efficacy of pancrealipase (PEZ) compared with placebo in the reduction of postprandial irritable bowel syndrome-diarrhoea (IBS-D). Design An intention to treat, double blind, randomised, crossover trial comparing PEZ to placebo for reduction of postprandial IBS-D. Patients had to recognise at least two different triggering foods, be willing to consume six baseline ‘trigger meals’ and again blinded with PEZ and placebo. Patients then chose which drug they preferred for another 25 meals. Setting Outpatient internal medicine practice clinic. Patients 255 patients were screened; 83 met the criteria, including 5 years of symptoms, recognised ‘food triggers’, no other identifiable cause for the symptoms, either a normal colonoscopy or barium enema while symptomatic and able to discontinue all anticholinergic medications. 69 patients were enrolled, 20 withdrew before randomisation, leaving 49 patients: 14 men, 35 women, mean age 52 years (SD 15.3). Over 60% had experienced symptoms for 11–30 years and 16% for more than 40 years. Interventions After completing six baseline meals, patients were randomised in blocks of four to receive either identical PEZ or a placebo for another six meals, and after a washout period of time received the alternative drug. Main outcome measures The primary analysis was number of patients who chose PEZ over placebo for the extended use. Results Overall, 30/49 (61%) would have chosen PEZ (p=0.078), with first drug preference for PEZ at 0.002. Among the PEZ subgroup, PEZ use compared with placebo, demonstrated improvement in all symptoms (p≤0.001) for cramping, bloating, borborygami, urge to defecate, global pain and decrease stooling with increase in stool firmness. Conclusions PEZ was found in a small group of patients to reduce postprandial IBS-D symptoms and deserves further evaluation.

The MCP-1 –2518 A/G Polymorphism Is Not a Susceptibility Factor for Chronic Pancreatitis

Background and Aims: Chronic pancreatitis (CP) is an inflammatory process initiated by recurrent acute pancreatitis and characterized by progressive parenchyma destruction and fibrosis. Genetic factors influence susceptibility and modify progression. The monocyte chemotactic protein-1 (MCP-1) –2518 G allele, which modifies the severity of acute pancreatitis, was investigated as a susceptibility factor for CP. Methods: A genetic association study was performed on 177 CP patients and 116 healthy controls from the NAPS2 Study. The MCP-1 A/G genotype was determined by RFLP and confirmed by DNA sequencing. Results: Compared to the control group the MCP-1 –2518 genotypes were similar: A/A (57% vs. 50%), A/G (34.5% vs. 40%) and G/G (8.5% vs. 10%). These allele frequencies were not statistically different (p = 0.267). Conclusions: Although the pro-inflammatory chemokine MCP-1 –2518 G allele is a severity factor for AP, it does not significantly alter susceptibility to CP.

Known genetic susceptibility factors for chronic pancreatitis in patients of European ancestry are rare in patients of African ancestry

BACKGROUND Multiple pathogenic genetic variants are associated with pancreatitis in patients of European (EA) and Asian ancestries, but studies on patients of African ancestry (AA) are lacking. We evaluated the prevalence of known genetic variations in African-American subjects in the US. METHODS We studied prospectively enrolled controls (n = 238) and patients with chronic (CP) (n = 232) or recurrent acute pancreatitis (RAP) (n = 45) in the NAPS2 studies from 2000-2014 of self-identified AA. Demographic and phenotypic information was obtained from structured questionnaires. Ancestry and admixture were evaluated by principal component analysis (PCA). Genotyping was performed for pathogenic genetic variants in PRSS1, SPINK1, CFTR and CTRC. Prevalence of disease-associated variants in NAPS2 subjects of AA and EA was compared. RESULTS When compared with CP subjects of EA (n = 862), prevalence of established pathogenic genetic variants was infrequent in AA patients with CP, overall (29 vs. 8.19%, OR 4.60, 95% CI 2.74-7.74, p < 0.001), and after stratification by alcohol etiology (p < 0.001). On PCA, AA cases were more heterogeneous but distinct from EA subjects; no difference was observed between AA subjects with and without CP-associated variants. Of 19 A A patients with CP who had pathogenic genetic variants, 2 had variants in PRSS1 (R122H, R122C), 4 in SPINK1 (all N34S heterozygotes), 12 in CFTR (2 CFTRsev, 9 CFTRBD, 1 compound heterozygote with CFTRsev and CFTRBD), and 1 in CTRC (R254W). CONCLUSION Pathogenic genetic variants reported in EA patients are significantly less common in AA patients. Further studies are needed to determine the complex risk factors for AA subjects with pancreatitis.

Enzyme therapy for functional bowel disease-like post-prandial distress

Post‐prandial gastrointestinal symptoms such as diarrhea, abdominal distension, flatulence, bloating and a feeling of fullness are common complaints of often unknown etiology and pathogenesis. There is a long history of trials reporting the successful use of products containing a variety of combinations of digestive enzymes including a number of randomized placebo‐controlled trials. We provide a narrative review of studies describing the use of multi‐digestive enzymes for symptoms consistent with irritable bowel syndrome. We describe clinical trials reported over the past 60 years including double‐blinded randomized, placebo‐controlled studies and recent trials that focused on post‐prandial diarrhea consistent with diarrhea‐predominant irritable bowel syndrome. Disaccharidase deficiencies or deficiencies of other carbohydrate digesting enzymes were excluded. Worldwide studies have generally reported success with multi‐enzyme preparations although none used a factorial design to identify subgroups or attempted to link specific symptom responses to specific components of therapy. Although there is a long history of the successful use of multi‐enzyme preparations for post‐prandial symptoms consistent with irritable bowel syndrome, long‐term studies using validated scoring systems and factorial designs are needed to confirm the results for specific symptoms and the components of the combination drugs received.