Serine Protease Inhibitor Kazal Type 1 Mutation Research Articles

Hereditary Pancreatitis Related to SPINK-1 Mutation. Is There an Increased Risk of Developing Pancreatic Cancer?

It is thought that many of the idiopathic pancreatitis could have a genetic base.Approximately 50% of them correspond to CFTR (cystic fibrosis transmembrane conductance regulator gene) and SPINK-1 (serine protease inhibitor Kazal type 1) mutations.A recent study compares patients with acute pancreatitis andSPINK-1 mutation withpatients with idiopathic acute pancreatitis. The study highlights a12-fold increased risk of developing pancreatic cancer with SPINK-1 mutation versus the control group.Nonetheless, authors conclude that only specificpN34s mutation is related to pancreatic cancer. This relation is controversial, and international consensus guidelines for the follow-up in chronic pancreatitis with pancreatic cancer still do not recommend follow-up in SPINK-1 p. N34S mutation. We believe that developing prospective studies in which subgroups of patients with SPINK-1 mutation benefit from closer follow-ups would be necessary.

A high prevalence of genetic polymorphisms in idiopathic and alcohol-associated chronic pancreatitis patients in Ireland

Background: Rare pathogenic variants in serine protease inhibitor Kazal type-1 (SPINK1), cationic trypsinogen (PRSS1), cystic fibrosis transmembrane conductance regulator (CFTR) genes are strongly associated with the development and progression of chronic pancreatitis (CP), but are not routinely tested. For a considerable number of CP patients, the cause of disease is unknown or ambiguous despite sophisticated imaging and biochemical investigations. We hypothesised that some patients diagnosed with idiopathic or alcohol-induced CP may carry CP-related mutations. Therefore, we investigated the presence of CP-related gene mutations in idiopathic and alcohol-associated CP patients, compared to controls. Methods: 126 patients with idiopathic and alcohol-induced CP and 167 controls were enrolled following ethical approval. Mutations were assessed by Taqman© genotyping assay. The study was further reinforced by post hoc analysis of SPINK1 N34S with additional controls (total n=508). Results: Mutations were detected in 25 patients (19.8%) and 10 controls (6%)(P<0.001). The presence of a gene mutation increased disease risk three-fold (odds ratio (OR) 3.4). The majority of mutations were found in SPINK1 N34S (12.7%), which increased disease risk six-fold (OR 5.9). CFTR severe mutation (F508del) was present equally in patients and controls (P=0.746). CFTR mild variant (R117H) was not significantly represented amongst patients (P=0.169). PRSS1 variants were not detected in either group. SPINK1 N34S mutations were more common in patients (12.7%) than in controls (2.4% of n=508)(P=5*10-7). Conclusion: 20% of CP patients carried disease-associated / disease-modifying gene mutations, with SPINK1 N34S disease-altering mutation being unexpectedly high. We therefore suggest that the presence of a SPINK1 mutation should be considered in patients with idiopathic or alcohol-induced CP, particularly where diagnosis is uncertain. Early identification of the presence of variants will allow for modification of risk factors and improve CP management. Furthermore, identifying underlying heritable risk factors may contribute to improved options for disease prevention and treatment.

SPINK-1 Polymorphism as a Pancreatitis Risk Factor

Genetic etiologies are responsible for 10% of pancreatitis cases. Serine protease inhibitor Kazal-type 1 (SPINK-1) polymorphisms are seen in approximately 2% of the US population and are attributed to 5-6% of all chronic pancreatitis cases and 15-40% of idiopathic pancreatitis cases. On average, irrespective of gender, those with SPINK-1 polymorphisms who develop pancreatitis do so at a younger age (mid 20's) when compared to those without (mid 30's). A 56 y.o. male with a past medical history of recurrent chronic pancreatitis with heterogeneous SPINK-1 mutation (diagnosed at age 27) presented with severe left lower quadrant (LLQ) abdominal pain. The patient had 7 pancreatitis flares within the past year. He had a remote alcohol and smoking history though he denied recent use. On admission, the patient's vitals were within normal limits and physical exam was significant only for LLQ tenderness and hypoactive bowel sounds. Labs revealed AST 14 U/L, ALT 12 U/L, Alk Phos 63 U/L, lipase 43 U/L, total cholesterol 138 mg/dL, triglycerides 129 mg/dL, and INR 1.4. CT abdomen/pelvis w/ contrast revealed an enlarging known pseudocyst in the pancreatic tail measuring 3.4 x 5.3 cm as well as peripancreatic inflammatory changes surrounding the distal body and extending along the spleen. [Figure 1.] Patient saw resolution of symptoms post supportive management and IV hydration. The SPINK-1 gene encodes a trypsin inhibitor, which in those with a gene polymorphism, fails to adequately prevent trypsinogen from autoactivating and damaging the pancreas. [Figure 2] SPINK-1 mutations predispose patients to acute pancreatitis, earlier onset chronic pancreatitis, and pancreatic cancer. Mutations do not follow autosomal dominant or recessive patterns and heterozygotes and homozygotes display similar rates of disease process making the mutation a disease modifier rather than a direct cause. Treatment for hereditary pancreatitis is the same as that of other causes of pancreatitis. Rarely, in severe cases of chronic pancreatitis, pancreatectomy with islet cell transplantation is considered. Though regular genetic testing is not used for SPINK-1, early identification of those with polymorphisms may help lead to lifestyle modifications to reduce overall risk of disease development. Our patient's unfortunate history of pancreatitis is likely secondary to previous insults from alcohol and smoking in the setting of heterozygous SPINK-1 mutation.2899_A Figure 1. 5.2x2.7 cystic lesion was noted on initial CT abdomen with contrast. (Left) Subsequent CT abdomen with contrast two months later (on current admission) showed the lesion had increased to 5.3x 3.4cm. (Right)2899_B Figure 2. Pathogenesis of SPINK-1 polymorphism in the development of Pancreatitis.

Recurrent Acute Pancreatitis With Energy Drinks Consumption: Rare but Definite Association

Acute pancreatitis is the most common gastrointestinal cause of hospitalization in the United States. Gallstones and alcohol use account for approximately 80 percent of the cases and in remainder the etiology of acute pancreatitis remains unknown. Rare cases of energy drinks as a possible cause of acute pancreatitis have been reported. We report a case of recurrent acute pancreatitis from energy drinks A 19-year-old Caucasian male with Serine Protease Inhibitor Kazal-type 1 (SPINK1) gene mutation had recurrent bouts of acute mild interstitial pancreatitis, 10 admissions in the year of 2017. His presentations include acute onset of deep epigastric pain, lipase level of > 10,000 (u/l). Repeated imaging (Including magnetic resonance imaging with cholangiopancreatography) showed acute mild interstitial pancreatitis without any biliary or additional pancreatic pathology or changes suggestive of chronic pancreatitis. The triglycerides levels ranged from 50 to 77 mg/dL. All episodes responded to conservative management with aggressive fluid resuscitation and pain control without any complications. He was not on any medications or herbal supplement. IgG4 level was 32 mg/dL. He drank Full Throttle (contains taurine, ginseng extract, caffeine, carnitine fumarate, guarana extract) and Red Bull (contains taurine and caffeine) on regular basis. The patient was counselled to abstain from energy drinks. He has not had any recurrence since on 7 months follow-up. Based on strength of association, drugs are considered definite, probable or proposed cause of pancreatitis. Drug is considered as definite cause if patient develops pancreatitis while on the drug, improves on stopping and reoccurs when drug is reintroduced. This case met all the definition's criteria. Additionally, Ayoub et al. reported significant injuries to islet cells and pancreatic acini with energy drinks administration to albino rats. This confirms the biological plausibility of energy drinks causing acute pancreatitis. The mild nature of each of the pancreatitis episode is consistent with drug-induced pancreatitis. Presence of SPINK1 mutation increased this patient's susceptibility to develop acute pancreatitis but it doesn't cause pancreatitis by itself. Energy drinks have definite association with acute pancreatitis and should be discontinued in patients who are at high risk of developing acute pancreatitis such as patient with SPINK1 mutation.1442.tif Figure 1: No Caption available.

Comprehensive screening for PRSS1, SPINK1, CFTR, CTRC and CLDN2 gene mutations in Chinese paediatric patients with idiopathic chronic pancreatitis: a cohort study

ObjectiveGenetic alterations may contribute to chronic pancreatitis (CP) in Chinese young patients. This study was designed to investigate mutations of cationic trypsinogen (PRSS1), pancreatic secretory trypsin inhibitor or serine protease...

Presence of SPINK‐1 variant alters the course of chronic pancreatitis

There is growing evidence that genetic mutations/variants increase susceptibility to the development and progression of chronic pancreatitis (CP). Several mutations have been identified that have a direct and indirect role in events leading to CP. Mutations in the serine protease inhibitor, Kazal type-1 (SPINK-1) gene have been reported to lower the threshold for pancreatitis in the presence of other genetic or environmental factors. The prevalence and impact of SPINK-1 mutations on the clinical course and outcomes of CP remains unclear. This study was conducted to assess the prevalence of the SPINK-1/N34S variant in patients with CP, and to understand the impact of the SPINK-1 mutation on the natural history of CP. A retrospective-prospective analysis of 239 patients with CP was performed. A detailed history, including duration of symptoms, type of pain (intermittent flares or chronic continuous pain), number of flares requiring hospital admission, alcohol and smoking history, and family history was obtained. The baseline morphological stage of CP was categorized by Cambridge classification. Clinical outcome variables included frequency and severity of pain episodes, presence of exocrine failure (defined by presence of steatorrhea and/or fecal elastase < 200 ug/g), and diabetes. The genetic tests included the cationic trypsinogen gene-1 mutation, cystic fibrosis gene mutations (Genzyme assay), and the SPINK-1/N34S mutation. Of the 239 patients with CP, 13 (5.4%) were positive for the SPINK-1/N34S mutation. There were 35 (14.6%) patients with idiopathic pancreatitis (IP) in this cohort. Most of the patients who were positive for the SPINK-1/N34S mutation had IP and were Caucasian (69.2%). The patients with the SPINK-1/N34S mutation had a younger age of onset (32.9 ± 10.2 vs 40.1 ± 13.6 years; P = 0.108) than those with IP and no mutation. Over a median follow up of 9.6 years, the patients with the SPINK-1/N34S mutation had a significantly greater number of acute flares each year, as compared to those without the mutation (11.8 ± 1.5 vs 4 ± 0.98; P = 0.0001). The prevalence of the SPINK-1/N34S mutation in patients with CP is 5.4%, and is approximately 37.1% in patients with IP. These mutations are more prevalent in Caucasian patients with CP. The SPINK-1/N34S mutation predisposes to early onset IP and more frequent acute flares of pancreatitis that might ultimately lead to pancreatic insufficiency. The patients with IP and borderline alcohol history should be considered for testing for genetic analysis, including SPINK-1 mutations, initially restricted to clinical trials.

High Incidence of PRSS1 and SPINK1 Mutations in Korean Children With Acute Recurrent and Chronic Pancreatitis

We evaluated the frequencies and clinical consequences of mutations in the genes encoding cationic trypsinogen, serine protease 1 (PRSS1), and serine protease inhibitor Kazal type 1 (SPINK1) in children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). The study population consisted of 32 children with ARP or CP and 28 healthy controls. We analyzed clinical data and the sequences of the entire coding region and the intron-exon boundaries of the PRSS1 and SPINK1 genes from each patient. Fifteen (46.9%) of the 32 patients had at least 1 PRSS1 or SPINK1 mutation. Four (12.5%) of the 32 patients carried the p.N29I, p.R122H, or p.N29T mutation or a p.G208A variant of the PRSS1 gene in a heterozygote state. Eleven (34.4%) of the 32 patients carried either the IVS3 + 2T>C or p.N34S mutation of the SPINK1 gene. No PRSS1 or SPINK1 mutations were identified in the control group. In particular, mutations were identified in 4 of our patients who experienced pancreas divisum with CP, whereas the remaining 2 patients with pancreas divisum and ARP did not have mutation. The frequencies of the PRSS1 and SPINK1 mutations are relatively high in Korean children with ARP or CP. Mutations in the PRSS1 and SPINK1 genes are highly associated with the development of childhood ARP or CP. Our findings suggest that patients with genetic mutations combined with pancreas divisum tend to develop CP early.

Hereditary pancreatitis – managing patient clinical information and sequence variants in the CFTR, PRSS1 and SPINK1 genes

Hereditary pancreatitis is a rare inherited disorder, characterized by recurrent episodes of acute pancreatitis usually within the first two decades of life progressing to chronic pancreatitis. Disease progression includes pancreatic calcifications, exocrine insufficiency, and diabetes mellitus in most patients. Some cases progress to pancreatic cancer. The mode of inheritance suggests an autosomal dominance trait with incomplete penetrance. PRSSI is a one of eight trypsinogen genes. Mutations in the PRSS1 gene are believed to be mostly gain-of-function leading to increased activity or stability of trypsin and / or decreased trypsin inactivation resulting in autolysis of the pancreatic tissue. Almost all the PRSS1 pancreatitis-associated mutations discovered to date seem to cluster in exons 2 and 3. The two most common c.365G>A, p.R122H and c.86A>T, p.N29I are missense mutations and are reported to have a penetrance of 80% for hereditary pancreatitis. Two other genes, SPINK1 (serine protease inhibitor Kazal type 1) and CFTR are risk factors for pancreatitis. Mutations in these two genes may be inherited in an autosomal recessive or multifactorial fashion. SPINK1, is a specific trypsin inhibitor expressed within the pancreas, providing an important defense against prematurely activated trypsinogen. 15% of adults, and 25% of children, with idiopathic pancreatitis have SPINK1 mutations. The primary mutation found in the SPINK1 gene, c.101A>G, p.N34S, increases the risk for pancreatitis by 14 fold. Approximately 30% of individuals with idiopathic pancreatitis have at least one CFTR mutation. Hereditary pancreatitis is an autosomal disease with variable expression caused by mutations in the PRSS1 gene. Two other genes, SPINK1 and CFTR, are risk factors for pancreatitis and can be inherited in an autosomal recessive or multifactorial fashion. Gene sequencing of all three genes aids in the diagnosis of hereditary pancreatitis which can be difficult to distinguish from a mild cystic fibrosis phenotype. Manageability of data derived from the patient’s clinical presentation and sequencing results is vital to understand genotype/phenotype correlation, to help classify variants and to assure quality in laboratory reporting. To this end, we have employed the clinical data management software, Progeny, to track genotypic and phenotypic information on individuals and pedigrees. The database was customized for pancreatitis patients. Data entered includes patient demographics and clinical presentation, laboratory sequencing results (nucleotide and amino acid changes for CFTR, PRSS1 and SPINK1; mutation type and effect; and significance of the variant) and evidence for reclassification of variants. Analysis of 59 pancreatitis cases (classified as idiopathic, acute or chronic) found 10.2% of the patients carried one CFTR mutation, 5.1% carried one CFTR and one SPINK1 mutation, 5.1% carried one PRSS1 mutation, 1.7% carried two CFTR mutations, 1.7% carried one CFTR mutation and two SPINK1 mutations and 6.8% carried one SPINK1 mutation. No mutations were found in 69.5% of the cases. Progeny software allows customized databases for combining clinical and laboratory information, providing a means for accessible collection and querying of data. Samples Patient samples were sent to ARUP Laboratories (Salt Lake City, Utah) for clinical testing. Sequencing Patient samples requesting an idiopathic pancreatitis panel (IP panel) were sequenced in the clinical laboratory. An IP panel composed of full gene sequencing (FGS) for all three genes CFTR, PRSS1 and SPINK1 was ordered on 45 samples. Seven patient samples had FGS ordered only for PRSS1, 5 had FGS for SPINK1 only and 2 patient samples had FGS ordered both for PRSS1 and SPINK1. Thirty-three samples sent in for only CFTR FGS were selected for additional analysis due to their singular diagnosis of pancreatitis. The samples were de-identified and sequencing for PRSS1 and SPINK1 was performed in the R&D laboratory.

SPINK1, ADH2, and ALDH2 gene variants and alcoholic chronic pancreatitis in Japan

The serine protease inhibitor Kazal type 1 (SPINK1) is a potent antiprotease and an important inactivation factor of intrapancreatic trypsin activity. Loss of function by the SPINK1 mutations leads to decreased inhibitory capacity. The significance of SPINK1 mutations in alcoholic chronic pancreatitis (CP) in Japan and its functional role remain unclear. The aim of the present study was to clarify the incidence of SPINK1, alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) variants in CP patients in Japan. One hundred and 86 patients with CP, and 527 healthy volunteers were enrolled. Mutational analyses were performed by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. Serum pancreatic secretory trypsin inhibitor (PSTI) level was measured by radioimmunoassay. The frequencies of N34S and IVS3 + 2T > C in the SPINK1 gene were significantly higher in patients with non-alcoholic CP (12.9% and 8.6%, respectively) than in normal subjects (0.37% and 0%). In total, 18 of 93 (19.4%) patients with non-alcoholic CP had at least one SPINK1 mutation. Concerning alcoholic CP, we found IVS3 + 2T > C in a small number of patients (3.9%). Serum PSTI concentration was decreased in patients with the IVS3 + 2T > C mutation. The frequency of the ADH2*2 allele in the alcoholic CP group was significantly higher than that in alcoholics without pancreatitis. The frequency of the ALDH2*2 allele was significantly low in patients with alcoholic CP compared with healthy controls. In conclusion, SPINK1 mutations were associated with non-alcoholic CP. Furthermore, we revealed the amount of wild-type PSTI was decreased in patients with IVS3 + 2T > C mutation. Variants of alcohol-metabolizing enzymes appeared in the relation to alcoholic CP.

Identification of CFTR, PRSS1, and SPINK1 Mutations in 381 Patients With Pancreatitis

Chronic pancreatitis is a progressive inflammatory disorder leading to irreversible exocrine and/or endocrine impairment. It is well documented that mutations in the cationic trypsinogen (PRSS1) gene can cause hereditary pancreatitis. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) and the serine protease inhibitor Kazal type 1 (SPINK1) genes are also associated with pancreatitis. We analyzed 381 patients with a primary diagnosis of chronic or recurrent pancreatitis using the Ambry Test: Pancreatitis to obtain comprehensive genetic information for the CFTR, SPINK1, and PRSS1 genes. The results identified 32% (122/381) of patients with 166 mutant CFTR alleles, including 12 novel CFTR variants: 4375-20 A>G, F575Y, K598E, L1260P, G194R, F834L, S573C, 2789 + 17 C>T, 621+83 A>G, T164S, 621+25 A>G, and 3500-19 G>A. Of 122 patients with CFTR mutations, 5.5% (21/381) also carried a SPINK1 mutation, and 1.8% (7/381) carried a PRSS1 mutation. In addition, 8.9% (34/381) of all patients had 1 of 11 different SPINK1 mutations. Another 6.3% (24/381) of the patients had 1 of 8 different PRSS1 mutations. Moreover, 1.3% of the patients (5/381) had 1 PRSS1 and 1 SPINK1 mutation. A total 49% (185/381) of the patients carried one or more mutations. Comprehensive testing of the CFTR, PRSS1, and SPINK1 genes identified genetic variants in nearly half of all subjects considered by their physicians as candidates for genetic testing. Comprehensive test identified numerous novel variants that would not be identified by standard clinical screening panels.

Mutations in serine protease inhibitor Kazal type 1 are strongly associated with chronic pancreatitis.

Although chronic pancreatitis is associated with risk factors such as alcoholism, hyperparathyroidism, and hypertriglyceridaemia, little is known of the actual aetiology of the disease. It is thought that inappropriate activation of trypsinogen causes pancreatitis, and indeed in cases of hereditary pancreatitis mutations of cationic trypsinogen (PRSS1) have been described. As serine protease inhibitor Kazal type 1 (SPINK1) is a potent natural inhibitor of pancreatic trypsin activity, we hypothesised that SPINK1 mutations would be more common than expected among an unselected cohort of adult chronic pancreatitis patients. To detect the prevalence of SPINK1 mutations in a cohort of chronic pancreatitis patients. DNA was isolated from a cohort of 115 adult patients with chronic pancreatitis of alcoholic (n=72), hereditary (n=10), idiopathic (n=24), and miscellaneous (n=9) origin. We performed mutational analysis for two PRSS1 mutations (R122H, N29I) and four specific SPINK1 gene mutations (M1T, L14P, N34S, P55S) and compared the results with a control group of 120 healthy Dutch subjects. In six of the 10 patients that fulfilled the criteria for hereditary pancreatitis, but in none of the control subjects, mutations in the PRSS1 gene were found. In 14 patients we detected a SPINK1 mutation. Eleven patients were heterozygous for the N34S mutation and sequencing confirmed the homozygous state of N34S in a brother and sister. Two patients carried the P55S mutation, one as a compound heterozygote with N34S. The M1T and L14P SPINK1 mutations were not found in our cohort. The N34S mutation was detected in only two of 120 controls, while the P55S, M1T, and L14P mutations were absent in the same group. Patients with the N34S allele had a later onset of disease than those with PRSS1 gene mutations but earlier onset compared with the mutation negative group. Identification of SPINK1 mutations in 12.2% of patients with adult alcoholic and idiopathic chronic pancreatitis suggests an important role for SPINK1 as a predisposing factor in adult chronic pancreatitis.

Mutations in serine protease inhibitor kazai type 1 are strongly associated with chronic pancreatitis

Background: Although chronic pancreatitis is associated with risk factors such as alcoholism, hyperparathyroidism, and hypertriglyceridaemia, little is known of the actual aetiology of the disease. It is thought that inappropriate activation of trypsinogen causes pancreatitis, and indeed in cases of hereditary pancreatitis mutations of cationic trypsinogen (PRSS1) have been described. As serine protease inhibitor Kazal type 1 (SPINK1) is a potent natural inhibitor of pancreatic trypsin activity, we hypothesised that SPINK1 mutations would be more common than expected among an unselected cohort of adult chronic pancreatitis patients. Aims: To detect the prevalence of SPINK1 mutations in a cohort of chronic pancreatitis patients. Methods: DNA was isolated from a cohort of 115 adult patients with chronic pancreatitis of alcoholic (n=72), hereditary (n=10), idiopathic (n=24), and miscellaneous (n=9) origin. We performed mutational analysis for two PRSS1 mutations (R122H, N29I) and four specific SPINK1 gene mutations (M1T, L14P, N34S, P55S) and compared the results with a control group of 120 healthy Dutch subjects. Results: In six of the 10 patients that fulfilled the criteria for hereditary pancreatitis, but in none of the control subjects, mutations in the PRSS1 gene were found. In 14 patients we detected a SPINK1 mutation. Eleven patients were heterozygous for the N34S mutation and sequencing confirmed the homozygous state of N34S in a brother and sister. Two patients carried the P55S mutation, one as a compound heterozygote with N34S. The M1T and L14P SPINK1 mutations were not found in our cohort. The N34S mutation was detected in only two of 120 controls, while the P55S, M1T, and L14P mutations were absent in the same group. Patients with the N34S allele had a later onset of disease than those with PRSS1 gene mutations but earlier onset compared with the mutation negative group. Conclusion: Identification of SPINK1 mutations in 12.2% of patients with adult alcoholic and idiopathic chronic pancreatitis suggests an important role for SPINK1 as a predisposing factor in adult chronic pancreatitis.