SPINK1 Mutations Research Articles

THE ROLE OF IDENTIFICATION OF SPINK1 GENE MUTATION STATUS IN PATIENTS WITH ACUTE PANCREATITIS OF ALIMENTARY GENESIS FOR THE PREDICTING THE SEVERITY OF CLINICAL COURSE AND FORMATION OF COMPLICATIONS

Мета роботи. Встановити частоту мутаційного статусу гена SPINK1 у пацієнтів з гострим панкреатитом аліментарного генезу та визначити прогностичну цінність алельного стану гена щодо оцінки ступня важкості та формування ускладненого перебігу.
 Матеріали та методи. Обстежено 70 хворих з гострим аліментарним панкреатитом, 48 (68,57%) чоловіків та 22 (31,43%) жінок. Середній вік 45,4 ± 13,87 років. Важкий перебіг гострого панкреатиту встановлено у 34 (48,57%) осіб, у 25 (35,72%) – середній, у 11 (15,71%) – легкий. Ускладнений перебіг гострого панкреатиту зафіксовано у 59 (84,29%) хворих групи, у решти – 11 (15,71%) перебіг мав неускладнений характер. Важкість перебігу та структуру ускладнень оцінювали за допомогою класифікації Атланта (2012). Для прогнозування важкості гострого панкреатиту проводили повторні вимірювання рівнів паличкоядерних нейтрофілів, амілази та глюкози. Статистичний аналіз виконували за допомогою програми STATISTICA (StatSoft Statisticа v.10).
 Результати. Мутації гена SPINK1 частіше зустрічались у пацієнтів з гострим аліментарним панкреатитом важкого – 16 (47,06%) та середнього ступеня важкості – 8 (32,0%), (р = 0,02). Наявність мутаційного статусу SPINK1 асоційована з достовірно вищими шансами важкого перебігу (OR = 3,11, CI (1,08–8,92), р = 0,03). У пацієнтів з гетерозиготними мутаціями SPINK1 встановлено достовірно вищі шанси формування панкреатичного скупчення (OR = 4,5, CI (1,36–14,93), p = 0,01), псевдокісти (OR = 3,58, CI (1,01–12,74), p = 0,04) та емпієми плеври (OR = 15,0, CI (1,56–143,83), p = 0,004).
 Носії гомозиготних мутацій SPINK1 мають вищі ризики розвитку перитоніту (OR = 12,89, CI (1,01–164,48), p = 0,04), плевриту (OR = 12,89, CI (1,01–164,48), p = 0,04) та системних ускладнень (OR = 2,61, CI (2,14–13,14), p = 0,02).
 Висновки. Встановлено високу інформативність ідентифікації мутаційного статусу гена SPINK1 у пацієнтів з гострим панкреатитом аліментарного генезу щодо прогнозування ступеня важкості запального процесу та формування ускладненого перебігу.

Pancreatitis associated with SPINK1 mutation and pancreaticobiliary maljunction

Abstract Chronic pancreatitis (CP) in childhood is a rare condition and its etiology varies with mainly associated with genetic abnormalities, autoimmune pancreatitis, and obstruction. The authors describe a 6-year-old girl presented with abdominal pain and diagnosed as CP with an infected peripancreatic fluid collections (peri-PFC), and found a pancreaticobiliary maljunction (PBM) together with a SPINK 1 mutation at N34S codon. This combination of an anatomical obstruction and genetic mutation should be aware, in early childhood presented with pancreatitis.

Natural history of SPINK1 germline mutation related-pancreatitis

BackgroundThe aim was to describe genetic, clinical and morphological features in a large, multicentre European cohort of patients with SPINK1 related pancreatitis, in comparison with patients with idiopathic pancreatitis (IP).MethodsAll SPINK1 mutation carriers with pancreatic symptoms from two French and one English centers were included. Patients with IP were included in a control group. Genetic, clinical, radiological and biochemical data were collected.Findings209 and 302 patients were included in the SPINK1 and control groups (median follow-up: 8.3 years (3.7–17.4) vs 5.3 (2.5–8.8)).The median age at onset of symptoms was 20.1 years (17.5–22.8) in the SPINK1 group versus 41.2 (35.2–45.2). The age of exocrine pancreatic insufficiency (EPI) onset in the SPINK1 group was 49.5 (44.5–54.6) years vs. 65.2 (62.1–68.3), p < 0.001. SPINK1 patients with EPI were 5.3%, 14.7%, 28.3% and 52.4% at 20, 30, 40 and 50 years.Diabetes occurred 37.7 (33.3–42.1) years following the onset of symptoms in the SPINK1 group vs. 30.6 (17.3–43.8) (p = 0.002). SPINK1 patients with diabetes were 7.8%, 13.4%, 26.3% and 43.4% at 30, 40, 50 and 60 years.Seven patients (3.3%) developed pancreatic cancer in the SPINK1 group (versus 3 (0.99%), p = 0.1), at a median age of 60 vs 66 years. The cancer risk was 0.8% before 50 years, 11.9%, 27.7%, 51.8% at 60, 70 and 80 years and was 12 times higher than in controls (Cox HR 12.0 (3.0–47.8), p < 0.001).InterpretationSPINK1 related pancreatitis is associated with earlier onset and pancreatic insufficiencies. p.N34S SPINK1 may well be associated with cancer.

Cystic fibrosis and exocrine pancreatic insufficiency

Cystic fibrosis (CF) is a genetic disease affecting many organs including the gastrointestinal tract. While the pulmonary damage is the most life threatening, the pancreas is one of the first and most affected organs by CF. Mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene results in a reduced volume of pancreatic juice and hyperconcentration of macromolecules leading to precipitation in the duct lumina, causing obstruction and damage. The clinical presentation of individual cases depends on a combination of different CFTR mutations, potential presence of modifier genes mutations, and environmental factors. The CFTR mutations are historically divided into 5 classes - severe mutations (classes I-III) and mild mutations (classes IV-V). The CFTR functional status depends on the combined effects of both CFTR allels and the severity of the phenotype depends on the milder mutation. The majority of CF patients exhibit exocrine pancreatic insufficiency in early childhood because functional acinar tissue has been lost in utero or soon after birth. These patients rarely suffer from pancreatic complications such as recurrent acute pancreatitis and/or chronic pancreatitis which, on contrary, can occur in the minority of patients who possess residual pancreatic exocrine function. CFTR mutations are found more frequently in idiopathic and alcoholic chronic pancreatitis but the data is conflicting. A combination with SPINK-1 mutations can be found in idiopathic chronic pancreatitis group, as well as presence of environmental factors. Malnutrition is directly related to worse prognosis of CF patients and delivery of active digestive enzymes is a cornerstone of the treatment with acid supression and vitamins supplementation playing an important additional role.

Pancreas Divisum in Pediatric Acute Recurrent and Chronic Pancreatitis: Report From INSPPIRE.

The significance of pancreas divisum (PD) as a risk factor for pancreatitis is controversial. We analyzed the characteristics of children with PD associated with acute recurrent or chronic pancreatitis to better understand its impact. We compared children with or without PD in the well-phenotyped INSPPIRE (INternational Study group of Pediatric Pancreatitis: In search for a cuRE) cohort. Differences were analyzed using 2-sample t test or Wilcoxon rank sum test for continuous variables, Pearson χ or Fisher exact test for categorical variables. PD was found in 52 of 359 (14.5%) subjects, a higher prevalence than the general population (∼7%). Females more commonly had PD (71% vs. 55%; P=0.02). Children with PD did not have a higher incidence of mutations in SPINK1, CFTR, CTRC compared with children with no PD. Children with PD were less likely to have PRSS1 mutations (10% vs. 34%; P<0.01) or a family history of pancreatitis (P<0.05), and more likely to have hypertriglyceridemia (11% vs. 3%; P=0.03). Children with PD underwent significantly more endoscopic procedures and pancreatic sphincterotomy. Patients with PD had fewer attacks of acute pancreatitis (P=0.03) and were less likely to develop exocrine pancreatic insufficiency (P=0.01). Therapeutic endoscopic retrograde cholangiopancreatography was considered most helpful if pancreatic duct was impacted with stones (83% helpful). PD is likely a risk factor for acute recurrent pancreatitis and chronic pancreatitis in children that appears to act independently of genetic risk factors. Patients with PD and stones obstructing the pancreatic duct benefit most from therapeutic endoscopic retrograde cholangiopancreatography.

The prevalence of hereditary pancreatitis mutations in families with pancreatic cancer.

e15728 Background: Germline pathogenic variants (PV) in hereditary cancer risk genes are found in ~10-15% of pancreatic adenocarcinomas/cancers (PC), but most cases of familial PC have no identifiable genetic cause. Chronic pancreatitis is an established risk factor for PC, with a lifetime risk of PC of 10-30%, and has been associated with germline mutations in several genes: PRSS1, SPINK1, CASR, CTRC, and CFTR. Few studies have examined the prevalence of PV in the pancreatitis risk genes among patients reporting a personal or family history (FHx) of PC. Methods: The FCCC Risk Assessment Program (RAP) database was queried to identify patients tested for PRSS1, SPINK1, CASR, CTRC, and CFTR as part of risk assessment. Pedigrees, demographic and cancer history data were reviewed. De-identified data from Invitae on patients found to be CFTR+ on hereditary pancreatitis testing were also reviewed for personal/FHx of PC. Results: 26 patients with PC and 48 patients with a FHx of PC underwent germline testing for the pancreatitis genes at FCCC. 7 of 26 (26.9%) patients with PC carried at least one CFTR mutation, while 3 of 48 (6.3%) patients with a FHx of PC carried a CFTR mutation. Interestingly, 8 patients carried an intronic variant in the CFTR gene. No patients with PC and 2 of 48 (4.2%) patients with a FHx of PC carried a SPINK1 mutation. The CFTR mutation rate in PC patients exceeded the expected carrier rate (2.6-3.6%)(p &lt; 0.001). The SPINK1 mutation rate in PC patients also exceeded the expected carrier rate but was not statistically significant (1.9%)(p = 0.23). CaSR, PRSS1, and CTRC mutations were not identified in our population. Personal/FHx data were available to review for 175 of the 496 CFTR+ patients tested through Invitae. 49 of 175 (28%) had a personal history of PC and 105 of 175 (60%) had a reported FHx of PC. Strikingly, 23% of CFTR+ patients carried pathogenic mutations in other genes (most commonly SPINK1). Conclusions: In our select sample, CFTR mutations, and in particular a known intronic variant, were highly enriched in a population of patients undergoing risk assessment for hereditary PC. Commercial data suggest a substantial minority of CFTR+ carriers with a personal/FHx of PC may also carry SPINK1 mutations.

Genetic variants in acute, acute recurrent and chronic pancreatitis affect the progression of disease in children

Background/objectivesAcute pancreatitis (AP) is emerging in pediatrics. A subset of children with AP progresses to acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). The role of extensive gene testing in the progression has not been investigated previously. We have followed children enrolled in the registry and at our center for progression to ARP and CP after the first attack. MethodsThis study utilizes an extensive gene sequencing panel as a platform to evaluate the role of genetics in first attack AP, and the progression over time, from first attack to ARP and CP in children. ResultsGenes, with corresponding variants were involved in the 3 groups studied: AP, ARP and CP. We have shown that the presence of gene variants from the eight tested genes is enriched in the CP group compared to the AP and ARP groups. The presence of more than one gene was associated with CP (p = 0.01). SPINK1 mutation(s) was significantly associated with faster progression to ARP, (p = 0.04). Having a variant from CFTR, SPINK1 or PRSS1, was associated with the faster progression from AP to CP over time (p < 0.05). ConclusionsThis study shows that genetics have a significant role in progression to ARP and CP from the first attack of pancreatitis.

Diagnosis of Colon Polyps Using Artificial Intelligence: Accurate Classification of Diminutive Polyps

It has been found that mutations of cationic trypsinogen gene (PRSS1) and serine protease inhibitor, Kazal type 1 gene (SPINK1) increase the susceptibility of chronic pancreatitis (CP). Specifically, mutations in the PRSS1 gene are related to the occurrences of hereditary and idiopathic pancreatitis while SPINK1 mutations are known to act as a disease modifier and are associated with idiopathic CP. However, the association of SPINK1 mutations with alcoholic CP is still controversial. We investigated the prevalence of PRSS1 and SPINK1 mutations in idiopathic and alcoholic CP in Korea.Seventy-one Korean patients with CP (alcoholic: 47, idiopathic: 22 and familial: 2) and 19 controls were included in this studies. Genomic DNA was extracted from peripheral blood of the patients. Mutations of SPINK1 (exon 3: N34S) and PRSS1 (exon 2: N29I, exon 3: R122H) genes were detected by PCR-RFLP methods. For the detection of SPINK1 mutation, restriction endonuclease PstI and BsrDI were used, while Sau3A and AflIII were used for the defection of PRSS1 mutation.Only one patient (2.1%) with alcoholic CP was a heterozygote for SPINK1 (N34S) mutation. Mutation in the PRSS1 (N29I, R122H) gene was not found in any group of CP patients. Additionally, we could not find any mutations of SPINK1 or PRSS1 in the control group.SPINK1 and PRSS1 mutations are not related to the development of CP in Korea.

Spink1 Mutation in Idiopathic Recurrent Acute Pancreatitis-Pilot Study

Spink1 Mutation in Idiopathic Recurrent Acute Pancreatitis-Pilot Study

CTRC gene polymorphism may increase pancreatic cancer risk - preliminary study.

To analyze selected SPINK1, CTRC, CFTR, and PRSS1 gene mutations in cancer tissue and blood samples of patients with pancreatic tumors. We enrolled 16 consecutive patients diagnosed with pancreatic tumors. We collected cancer tissue, normal pancreatic tissue, and blood samples for genetic tests. The control group consisted of 419 healthy individuals. Peripheral blood samples were collected from all study participants in EDTA-coated tubes. Out of 16 patients with pancreatic tumors, 12 had pancreatic cancer on microscopic examination (mean age, 60.2 years). The CTRC polymorphism Hetero p.G60=(c.180C&gt;T) was found in 5 patients with pancreatic cancer (41.7% vs. 18.6% in the control group). One patient with pancreatic cancer and a positive family history had the SPINK1 (p.N34S) mutation [8.3% vs. 2.9% (12/419) in the control group]. One patient with pancreatic cancer had the CTRC (p.R254W) mutation [8.3% vs. 1% (4/419) in the control group]. Our preliminary results show that the CTRC polymorphism p.G60= (c.180C&gt;T) is frequent in patients with pancreatic cancer. However, further research is needed to verify our findings.

Assessment of CFTR, SPINK1 and PRSS1 mutations, smoking and alcohol abuse in adult chronic pancreatitis patients from Barcelona.

Pancreatic enzyme replacement therapy (PERT) is indicated in case of clinically relevant exocrine pancreatic insufficiency (EPI). Clinical trials addressing PERT have used the coefficient of fat absorption (CFA) to define EPI but this test is cumbersome to perform. Our aim was to compare two easier-to-perform tests to detect clinically relevant EPI: Fecal Elastase-1 (FE-1) and 13C-Mixed Triglyceride Breath Test (TGBT).We prospectively included 54 patients with chronic pancreatitis (CP), 24.1% operated, 29.6% had EPI. EPI was defined as a CFA <93%. The sensitivity (Se), specificity (Sp), positive (PPV) and negative (NPV) predictive values for different cut-offs of FE-1 and TGBT were calculated.The area under the ROC curve for FE-1/TGBT was 0.861/0.876 for the global sample, 0.842/0.794 for non-operated patients and 0.917/1 for operated patients respectively. Se, Sp, PPV and NPV for a cut-off of FE-1 <200 μg/g were 93.8%, 63.2%, 51.7% and 96% respectively. The best cut-off point for FE-1 was 84 μg/g, which yielded an 87.5% Se, 81.6% Sp, 66.7% PPV and 93.9% NPV. The same parameters for a TGBT <29% were 81.3%, 84.2%, 68.4% and 91.4% respectively. The best cut-off point for TGBT was <23%, which yielded an 81.3% Se, 94.7% Sp, 86.7% PPV and 92.3% NPV. Diabetes was associated to decreased FE-1 levels, even in multivariate analysis.FE-1 and TGBT showed similar results for the diagnosis of EPI in CP. In non-operated CP patients, TGBT does not offer any advantage to FE-1 but in operated CP patients TGBT seems a more accurate test.

Nationwide survey of hereditary pancreatitis in Japan.

Hereditary pancreatitis (HP) is a rare cause of chronic pancreatitis. We here report a nationwide survey to clarify the epidemiological, genetic, and clinical features of HP in Japan. Target subjects were patients with HP and their family members who had visited selected hospitals between 2005 and 2014. This study consisted of two-stage surveys; patients with HP were identified by the first questionnaire and their clinical features were assessed by the second questionnaire. Two hundred seventy-one patients (153 males and 118 females) in 100 families diagnosed based on the Japanese criteria or 231 patients (131 males and 100 females) patients in 80 families based on the EUROPAC criteria were reported. Of the familiesundertaking genetic tests, 41% had the PRSS1 mutations (p.R122H 33%, p.N29I 8%) and 36% had the SPINK1 mutations (p.N34S 22%, c.194+2T>C 14%, p.P45S 1%). The mean age at symptom onset was 17.8years. The cumulative rates of pancreatic exocrine insufficiency and diabetes mellitus were 16.1 and 5.5% at 20years old, and 45.3 and 28.2% at 40years, respectively. Forty-four percent of the patients underwent endoscopic treatment and/or surgery. The cumulative rate of pancreatic cancer diagnosis was 2.8% at 40years old, 10.8% at 60years, and 22.8% at 70years. HP was characterized by early disease onset, frequent development of pancreatic exocrine insufficiency and diabetes mellitus, requirement of endoscopic treatment and/or surgery, and increased risk of pancreatic cancer. PRSS1 and SPINK1 mutations serve as genetic background for HP in Japan.

Etiology of Recurrent Acute Pancreatitis: 10-year Review from a Large Tertiary Hospital

Background: Recurrent acute pancreatitis (RAP) is an important spectrum of pancreatitis. Most studies of RAP focused on idiopathic recurrent acute pancreatitis (IRAP); RAP that remains idiopathic after ruling out causes by routine investigations. Studies on the etiology of overall RAP are lacking. Objective: To determine the etiology of RAP in a single tertiary hospital in Thailand. Methods: Medical records, imaging and endoscopic data of patients who presented with acute pancreatitis for more than once during 2005-2014 were retrospectively reviewed and analyzed. Results: There were 67 RAP patients over the 10-year period. Majority (68.7%) were men. Mean age was 47 ± 18 years. Thirty percent smoked and 47% drank significant alcohol (defined as ethanol >80 g/day for >5 years). Liver function test, serum triglyceride and calcium were done in every case. Ultrasonography, computed tomography and endoscopic ultrasonography were performed in 55.2%, 52.2% and 32.8%, respectively. Genetic study ( PRSS1 and SPINK1 mutations) were performed in 9 patients (13.4%) and mutations were found for PRSS1 in 1 and SPINK1 in 2 patients. Alcohol was the most common etiology of RAP (40.2%), followed by biliary stone (28.3%), all of which were macrolithiasis. ICP was the third most common cause (9.0%) and hereditary pancreatitis was diagnosed in 1 patient (1.5%). Seventeen patients (25.4%) had miscellaneous etiologies and 2 (2.9%) finally had IRAP. More than half (58%) of patients with RAP from macrolithiasis were associated with delayed cholecystectomy after the sentinel gallstone pancreatitis. Conclusion: The most common etiologies of RAP in order were alcohol, macrolithiasis and ICP. Among RAP patients from macrolithiasis, the main cause was delayed cholecystectomy after sentinel gallstone pancreatitis.

Natural history of pancreatitis associated with SPINK1 mutations

Background & Aims: Gain-of-function trypsin mutations cause acute pancreatitis and chronic pancreatitis. Loss of trypsin inhibitor function may have similar effects. We investigated the prevalence of SPINK1 (PSTI) mutations in familial pancreatitis, idiopathic chronic pancreatitis, and controls. Methods: Genetic-linkage studies were performed in 5 familial pancreatitis families. The entire SPINK1 gene was sequenced in 112 affected individuals and 95 control DNA samples, and exon 3 was sequenced in 95 additional controls. X-ray crystallography–based model building and statistical studies were performed. Results: Significant linkage between pancreatitis and 5q31.1-2 was excluded. Novel SPINK1 mutations, one D50E mutation, one IVS3+125 C>A, and five IVS3+184 T>A intronic polymorphisms were identified. The N34S and P55S mutations were observed in 29 of 112 patients (25%) as N34S/N34S (n = 7), N34S/wt (n = 19), N34S/P55S (n = 2), and N34S/D50E (n = 1). Three hundred eighty control alleles revealed 3 N34S (0.77%), 2 P55S (0.53%), and no D50E mutations. Age of disease onset and severity were similar between homozygous and heterozygous patients. Structural modeling revealed several possible pathophysiologic mechanisms for the N34S mutation. Conclusions: SPINK1 mutations are common in the population (~2%), but are clearly associated with pancreatitis. The mutation-associated risk is low. Modeling and familial clustering suggest that SPINK1 mutations are disease modifying, possibly by lowering the threshold for pancreatitis from other genetic or environmental factors, but by themselves do not cause disease.GASTROENTEROLOGY 2000;119:615-623

Assessment of CFTR, SPINK1 and PRSS1 mutations, smoking and alcohol abuse in adult chronic pancreatitis patients seen in Barcelona

Assessment of CFTR, SPINK1 and PRSS1 mutations, smoking and alcohol abuse in adult chronic pancreatitis patients seen in Barcelona

Is acute recurrent pancreatitis in children a precursor of chronic pancreatitis? A long-term follow-up study of 93 cases

Background/aimsIn view of paucity of literature we analyzed our experience of acute recurrent pancreatitis (ARP) to study clinical profile and long-term outcome. MethodsOver 13 years, 93 consecutive children (≤18 years) diagnosed to have ARP were included in this study. Magnetic resonance cholangiopancreatography was done at baseline and on follow-up. Common mutations for serine-protease-inhibitor (SPINK1 N34S), protease inhibitor (PRSS1 R122S) and cystic fibrosis transmembrane conductance regulator (CFTR deltaF508, 5T) were studied in 22 idiopathic cases. ResultsThe median age of the children with ARP was 13 (10–14.5) years, 53 were males. Etiology included biliary in 14 (15%), pancreas divisum in 6 (7%), others in 3 (3.5%) and idiopathic in the remaining 70 (75%). SPINK1 mutation was found in 10/22 (45%) cases. Over a median follow-up of 25.5 (8.25–48) months, 37 (42%) of 88 (5 lost to follow-up) developed chronic pancreatitis (CP). On multivariate analysis idiopathic etiology (p<0.03), presence of SPINK1 mutation (p=0.01), longer follow-up (p<0.001) were associated with progression to CP. ConclusionsBiliopancreatic structural/obstructive causes should always be looked for. It seems ARP is a precursor of CP and progression is associated with idiopathic etiology and presence of genetic mutations. Hence, patients with ARP should be kept on regular follow-up to detect CP.

CTRC gene polymorphism (p.G60=; c.180 C\u2009>\u2009T) in acute pancreatitis

BackgroundThe aim of the study was to determine the relationship between the presence of p.G60 = polymorphism (c.180C > T; rs497078) CTRC and the incidence together with the clinical course of acute pancreatitis (AP).MethodsTwo hundred ninety-nine people suffering from AP and 417 healthy volunteers were subjected to the study. DNA was isolated from blood samples.ResultsCTRC p.G60 = polymorphism (c.180C > T) occurred more frequently in the AP group (p = 0.015). The CT and TT genotype was found in 27.8% of the AP patients and in 19.9% of the healthy subjects (p = 0.017). No significant correlation was found between having the CT and TT genotype and the severity of the AP clinical course. In 6 patients (2%) with the CT genotype, a SPINK1 gene mutation was found, while in the control group it was found in 3 patients (0.7%), (p > 0.05). All patients with the present SPINK1 mutation with the CT genotype had a moderate or a severe course of the disease (p = 0.0007).ConclusionsCTRC polymorphism Hetero p.G60=; c.180C > T increases the risk of an AP occurrence and together with the SPINK 1 mutation, may be responsible for a more severe course of the disease.

Analysis of polymorphic variants of CFTR (rs 113993960), IL-4 (rs 2243250), PRSS1 (rs 111033565), SPINK1 (rs ID 6690) and TNF-α (rs 1800629) Genes in Patients with Edematous Pancreatitis Living in Northern Bukovyna region

The occurrence of gene mutations affecting the formation of acute pancreatitis or exacerbation of chronic pancreatitis differs in different populations and ethnic groups.The objective of the research was to study the incidence of CFTR (rs 113 993 960), IL-4 (rs 2243250), PRSS1 (rs 111 033 565), SPINK1 (rs ID 6690) and TNF-α (rs 1800629) gene mutations in Northern Bukovyna region and their dependence on etiological factor, sex and type of pancreatitis.Material and methods. Determination of IL-4 (C-590T), TNF-α (G-308A), PRSS1 (R122H), SPINK1 (N34S) and CFTR (delF508) genes polymorphisms was performed in 123 patients with acute pancreatitis and the exacerbation of chronic pancreatitis and in 40 healthy individuals.Results. The relative incidence of PRSS1, CFTR, SPINK1 and TNF-α genes polymorphisms in patients with acute pancreatitis and the exacerbation of chronic pancreatitis did not significantly differ. Carriers of CC genotype of IL- 4 gene were present among the patients with acute pancreatitis and in the control group by 22.39% and 21.76% more often than among the patients with the exacerbation of chronic pancreatitis. Acute alcohol-related pancreatitis was observed in men significantly more often than gallstone pancreatitis, namely by 53.58% in carriers of “wild” GG-genotype of PRSS1 gene, by 29.64% in carriers of CC genotype of IL-4 gene, by 42.40% in carriers of NN-genotype of CFTR gene, and by 38.74% in carriers of GG-genotype of SPINK1 gene, respectively.Conclusions. The mutation of CFTR (rs 113 993 960), PRSS1 (rs 111 033 565), SPINK1 (rs ID6690) and TNF-α (rs1800629) gene in the homozygous state among the population of Northern Bukovyna was not detected. Acute alcohol-related pancreatitis was more often diagnosed in men in case of “wild” genotypes of PRSS1, CFTR and SPINK1 genes, whereas gallstone pancreatitis was more often diagnosed in women.

Genetic Mutations in Pediatric Pancreatitis.

The aim of our study was to describe the prevalence, characteristics, and outcomes of children with acute recurrent (ARP) or chronic (CP) pancreatitis with or without mutations in PRSS1, CFTR or SPINK1. Retrospective chart review of children with ARP or CP with and without testing for PRSS1, CFTR, and SPINK1. Demographics, clinical features, management, and outcome were collected. Analysis of variance was used to compare continuous variables and χ or Fisher exact test for categorical variables. Ninety-one subjects with ARP (n = 77) or CP (n = 14) were identified and included in this study. Of these, 37 (41%) were male, 44 were white, and 30 were Hispanic. Thirty-three (36%) had at least 1 mutation identified (Pan-Mut): PRSS1 (7), CFTR (21), SPINK1 (3), SPINK/CFTR (2). Thirty-six were tested but had no mutation, and 22 were not tested. The Pan-Mut subjects were more likely to have a family history of pancreatitis but there were no differences in the clinical features, imaging or outcome. Mutations in CFTR, SPINK1 or PRSS1 are present in one third of pediatric ARP and CP with no other cause. No clinical features or outcomes differentiated between the Pan-Mut group and the no-mutation group. The Pan-Mut subjects were more likely to have a family history of pancreatitis. Pediatric ARP and CP without identified cause should undergo genetic testing.

Risk Factors Associated With Pediatric Acute Recurrent and Chronic Pancreatitis: Lessons From INSPPIRE.

Pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) are poorly understood. To characterize and identify risk factors associated with ARP and CP in childhood. A multinational cross-sectional study of children with ARP or CP at the time of enrollment to the INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a Cure) study at participant institutions of the INSPPIRE Consortium. From August 22, 2012, to February 8, 2015, 155 children with ARP and 146 with CP (aged ≤19 years) were enrolled. Their demographic and clinical information was entered into the REDCap (Research Electronic Data Capture) database at the 15 centers. Differences were analyzed using 2-sample t test or Wilcoxon rank sum test for continuous variables and Pearson χ2 test or Fisher exact test for categorical variables. Disease burden variables (pain variables, hospital/emergency department visits, missed school days) were compared using Wilcoxon rank sum test. Demographic characteristics, risk factors, abdominal pain, and disease burden. A total of 301 children were enrolled (mean [SD] age, 11.9 [4.5] years; 172 [57%] female); 155 had ARP and 146 had CP. The majority of children with CP (123 of 146 [84%]) reported prior recurrent episodes of acute pancreatitis. Sex distribution was similar between the groups (57% female in both). Hispanic children were less likely to have CP than ARP (17% vs 28%, respectively; odds ratio [OR] = 0.51; 95% CI, 0.29-0.92; P = .02). At least 1 gene mutation in pancreatitis-related genes was found in 48% of patients with ARP vs 73% of patients with CP (P < .001). Children with PRSS1 or SPINK1 mutations were more likely to present with CP compared with ARP (PRSS1: OR = 4.20; 95% CI, 2.14-8.22; P < .001; and SPINK1: OR = 2.30; 95% CI, 1.03-5.13; P = .04). Obstructive risk factors did not differ between children with ARP or CP (33% in both the ARP and CP groups), but toxic/metabolic risk factors were more common in children with ARP (21% overall; 26% in the ARP group and 15% in the CP group; OR = 0.55; 95% CI, 0.31-0.99; P = .046). Pancreatitis-related abdominal pain was a major symptom in 81% of children with ARP or CP within the last year. The disease burden was greater in the CP group compared with the ARP group (more emergency department visits, hospitalizations, and medical, endoscopic, and surgical interventions). Genetic mutations are common in both ARP and CP. Ethnicity and mutations in PRSS1 or SPINK1 may influence the development of CP. The high disease burden in pediatric CP underscores the importance of identifying predisposing factors for progression of ARP to CP in children.