Maiken Thyregod Joergensen

Genetic, epidemiological, and clinical aspects of hereditary pancreatitis: a population-based cohort study in Denmark.

OBJECTIVES:In a population-based, well-defined group of patients first regarded as having pancreatitis of unknown origin (PUO), we identified, described, and compared the clinical and genetic aspects of patients with hereditary pancreatitis (HP) and with cystic fibrosis transmembrane conductance regulator gene (CFTR) and serine protease inhibitor Kazal type 1 gene (SPINK1) mutations with patients who retained the diagnosis of true idiopathic pancreatitis (tIP) after genetic testing for HP, SPINK1, and CFTR mutations.METHODS:Patients with PUO were identified in the Danish National Registry of Patients or were referred by clinicians. DNA from blood was analyzed for cationic trypsinogen (PRSS1), SPINK1, and CFTR mutations. Considering the diagnosis of HP, a pedigree was drawn for each patient.RESULTS:A genetic mutation was found in 40% of 122 patients with PUO. After testing first-degree relatives of the 18 initially identified HP patients, 38 HP patients in total were identified, and 28 patients had SPINK1–CFTR mutations. Among HP patients, no p.N29I mutations were found and the p.A16V mutation was more frequent than previously reported, 45 and 32% had exocrine and endocrine insufficiency, respectively, and among tIP patients 9 and 12%, respectively. Pancreatic cancer was diagnosed in 5% of the HP families.CONCLUSIONS:The genotype of the Danish population with HP differs from that of previously described cohorts. The occurrence of exocrine and endocrine insufficiency is higher among patients with HP than in patients with SPINK1–CFTR mutations and tIP, and more HP families develop pancreatic cancer. Genetic testing thus helps to predict the prognosis of the pancreatitis.

The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families

Objective To characterise the phenotypes associated with the p.A16V mutation of PRSS1. Design Clinical and epidemiological data were collected for any family in which a p.A16V mutation was identified, either referred directly to the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer or via a collaborator. DNA samples were tested for mutations in PRSS1, SPINK1, CFTR and CTRC. Patients Participants were recruited on the basis of either family history of pancreatitis (acute or chronic) or the results of genetic testing. Families were categorised as having hereditary pancreatitis (HP), idiopathic disease or pancreatitis in a single generation. HP was defined as ≥2 cases in ≥2 generations. Main outcome measures Onset of painful episodes of pancreatitis, death from pancreatic cancer, diagnosis of diabetes mellitus and exocrine pancreatic failure. Results Ten families with p.A16V mutations were identified (22 affected individuals): six HP families, three with idiopathic disease and one with only a single generation affected. The median age of onset, ignoring non-penetrants, was 10 years (95% CI 5 to 25). There were eight confirmed cases of exocrine failure, four of whom also had diabetes mellitus. There were three pancreatic cancer cases. Two of these were confirmed as p.A16V carriers, only one of whom was affected by pancreatitis. Those with p.A16V pancreatitis were compared to affected individuals with p.R122H, p.N29I and no PRSS1 mutation. No significant differences were proven using logrank or Mann–Whitney U tests. Conclusions Penetrance of p.A16V is highly variable and family dependent, suggesting it contributes to multigenic inheritance of a predisposition to pancreatitis.

Cell-free Plasma microRNA in Pancreatic Ductal Adenocarcinoma and Disease Controls

Objectives There are no tumor-specific biochemical markers for pancreatic ductal adenocarcinoma (PDAC). Tissue-specific gene expression including microRNA (miRNA) profiling, however, identifies specific PDAC signatures. This study evaluates associations between circulating, cell-free plasma-miRNA profiles and PDAC in a disease and disease-control cohort. Methods We performed a microarray profiling of 847 different mature miRNAs from plasma in an exploratory cohort of 20 patients with PDAC or other pancreatic diseases, profiling of 45 miRNAs in plasma samples from PDAC (n = 48) and disease controls (n = 47), and evaluation of associations of data with diagnosis, survival, and CA-19-9. Results We find 7 significantly deregulated miRNAs in PDAC using univariate statistics. At a false-discovery rate of 5%, miRNA-375 remained significantly elevated in PDAC. MicroRNA-375 did not improve diagnosis of PDAC in this cohort (70% accuracy) and did not correlate with survival. However, 3 controls (other gastrointestinal cancers) with increased CA-19-9 did not show increased miRNA-375. Conclusions In the plasma-miRNA population, we find miRNA-375, which is selectively expressed in the endocrine pancreas under normal conditions, increased in PDAC cases compared with patients with other pancreatic or gastrointestinal diseases. The miRNA-375 does not outperform CA-19-9 diagnostically in the present cohort. However, it shows promising specificity and should be examined in larger prospective studies.

Comparison of plasma Tu-M2-PK and CA19-9 in pancreatic cancer.

Objectives: The performance of the 2 tumor markers carbohydrate antigen 19-9 (CA19-9) and tumor M2 pyruvate kinase (Tu-M2-PK) separately and in combination detecting pancreatic ductal adenocarcinoma (PDAC) was evaluated in a prospective study. Methods: The study comprised 103 patients referred because of suspicion of pancreatic cancer. Of these, 51 patients had their conditions diagnosed as PDAC, whereas this diagnosis was ruled out in 52 after 12 months of follow-up. The performance of Tu-M2-PK was compared with that of CA19-9 using cutoff values 15 and 37 U/mL, respectively. Results: The sensitivity of Tu-M2-PK and CA19-9 in detecting PDAC was 55% and 86% at specificities of 52% and 73%, respectively. The area under the curve (AUC) of Tu-M2-PK was 0.55 and that of CA19-9 was 0.84. Combining the 2 markers did not significantly improve AUC (AUC = 0.85, P = 0.72) compared with CA19-9 when used alone. The presence of chronic pancreatitis or jaundice causes increased levels of CA19-9 but does not influence Tu-M2-PK. Conclusions: Tu-M2-PK was inferior to CA19-9 as marker of PDAC. Tu-M2-PK may have a role in diagnosing PDAC because it is not affected by cholestasis or Lewis phenotype. Neither tumor marker can stand alone in the diagnosis of PDAC.

Intragenic duplication: a novel mutational mechanism in hereditary pancreatitis

Objectives: In a hereditary pancreatitis family from Denmark, we identified a novel intragenic duplication of 9 nucleotides in exon-2 of the human cationic trypsinogen (PRSS1) gene (c.63_71dup) which at the amino-acid level resulted in the insertion of 3 amino acids within the activation peptide of cationic trypsinogen (p.K23_I24insIDK). The aim of the present study was to characterize the effect of this unique genetic alteration on the function of human cationic trypsinogen. Methods: Wild-type and mutant cationic trypsinogens were produced recombinantly and purified to homogeneity. Trypsinogen activation was followed by enzymatic assays and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Trypsinogen secretion was measured from transfected HEK 293T cells. Results: Recombinant cationic trypsinogen carrying the p.K23_I24insIDK mutation exhibited greater than 10-fold increased autoactivation. Activation by human cathepsin B also was accelerated by 10-fold. Secretion of the p.K23_I24insIDK mutant from transfected cells was diminished, consistent with intracellular autoactivation. Conclusions: This is the first report of an intragenic duplication within the PRSS1 gene causing hereditary pancreatitis. The accelerated activation of p.K23_I24insIDK by cathepsin B is a unique biochemical property not found in any other pancreatitis-associated trypsinogen mutant. In contrast, the robust autoactivation of the novel mutant confirms the notion that increased autoactivation is a disease-relevant mechanism in hereditary pancreatitis.

Incidence, Etiology and Prognosis of First-Time Acute Pancreatitis in Young Patients: A Population-Based Cohort Study

Background/Aims: The etiology of acute pancreatitis (AP) seems to have changed during the last two decades, and since detection of mutations in the gene for cationic trypsinogen(PRSS1) causing hereditary pancreatitis some patients formerly diagnosed with idiopathic AP (IAP) turn out to have a genetic cause. Methods: Data on patients <30 years of age, diagnosed with AP identified in the Danish National Registry of Patients, were retrieved. Patients previously diagnosed with IAP were offered genetic counseling and testing for mutations in the PRSS1, the Serine Protease Inhibitor Kazal type1 (SPINK1) and the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR). Results: The standardized incidence ratio (SIR) of AP increased from 3.56 per 100,000 person-years in the period 1980–1984 to 6.43 in 2000–2004 (p < 0.01). The SIR of women surpassed that of men in 1999. Among patients with former IAP, 3 had hereditary pancreatitis, 3 CFTR and 4 SPINK1 mutations after re-evaluation. Conclusion: The incidence of AP, especially in women, increased over time. More patients had gallstone-related and less alcohol-related AP in the period 1999–2004 compared to 1980–1999. Genetic causes of AP were found in 32% of those tested with IAP and as a minimum estimation in 4% of the total cohort.

Is screening for pancreatic cancer in high-risk groups cost-effective? – Experience from a Danish national screening program

OBJECTIVE Pancreatic cancer (PC) is the fourth leading cause of cancer death worldwide, symptoms are few and diffuse, and when the diagnosis has been made only 10-15% would benefit from resection. Surgery is the only potentially curable treatment for pancreatic cancer, and the prognosis seems to improve with early detection. A hereditary component has been identified in 1-10% of the PC cases. To comply with this, screening for PC in high-risk groups with a genetic disposition for PC has been recommended in research settings. DESIGN Between January 2006 and February 2014 31 patients with Hereditary pancreatitis or with a disposition of HP and 40 first-degree relatives of patients with Familial Pancreatic Cancer (FPC) were screened for development of Pancreatic Ductal Adenocarcinoma (PDAC) with yearly endoscopic ultrasound. The cost-effectiveness of screening in comparison with no-screening was assessed by the incremental cost-utility ratio (ICER). RESULTS By screening the FPC group we identified 2 patients with PDAC who were treated by total pancreatectomy. One patient is still alive, while the other died after 7 months due to cardiac surgery complications. Stratified analysis of patients with HP and FPC provided ICERs of 47,156 US

Original articleIs screening for pancreatic cancer in high-risk groups cost-effective? – Experience from a Danish national screening program

vs. 35,493 US

Microscopic findings in EUS-guided fine needle (SharkCore) biopsies with type 1 and type 2 autoimmune pancreatitis

per life-year and 58,647 US

Incidence, Prevalence, Etiology, and Prognosis of First-Time Chronic Pancreatitis in Young Patients: A Nationwide Cohort Study

vs. 47,867 US