Hereditary Chronic Pancreatitis Research Articles

Endoscopic treatment of chronic pancreatitis in children: a retrospective study

Background. Chronic pancreatitis (CP) in children is a relatively rare polyetiological disease of the pancreas, accompanied by progressive inflammation of the parenchyma with gradual loss of its function and/or the occurrence of specific complications. Indications for a particular treatment method for a specific patient with a specific etiology and stage of CP are not clearly defined and largely depend on the experience and technical capabilities of a specific clinic. In recent years, individual centers have accumulated experience in using endoscopic methods for the treatment of CP in children, which seems very promising. Aim. To analyze the results of our experience in endoscopic treatment of CP in children. Materials and methods. From 2018 to June 2023, endoscopic treatment methods were used in 31 children with CP. Indications for endoscopic treatment were frequent episodes of exacerbation of pancreatitis in combination with signs of ductal hypertension with or without Wirsungolithiasis. According to etiology, patients were divided into groups: pancreatic duct anomalies, abnormal pancreaticobiliary junction (APBJ), hereditary CP, acquired duct strictures and idiopathic pancreatitis. The results were assessed by the frequency of episodes of exacerbation of pancreatitis. Results. Endoscopic treatment failed in two patients due to: impossibility of cannulation of the main pancreatic duct in a child operated on for annular pancreas and impossibility of recanalization of posttraumatic duct stricture in the isthmus area. Early complications included post-manipulation pancreatitis (n=2; 6.4%), asymptomatic hyperenzymemia (n=5; 16.1%), stent loss (n=2; 6.4%), stent obstruction with pancreatic precipitates (n=2; 6.4%). The average follow-up period was 2.31±1.32 years. In all groups except APBJ, there was a significant decrease in exacerbation episodes with their complete absence in most patients. Ineffectiveness of endoscopic treatment was noted in one case of a combination of the complete type of divided pancreas and a pathogenic mutation of the gene SPINK1. Thus, endoscopic treatment was effective in 28 (90.3%) children in the early period and in 22 (71%) in the late period due to the return of symptoms in the APBJ group. Conclusion. Endoscopic treatment of chronic pancreatitis in children is effective and can be recommended as first-line therapy. Endoscopic treatment of symptomatic APBJ has a temporary clinical effect.

An unusual type of diabetes “not 1” and “not 2”

Type 3c diabetes mellitus (T3cDM) is a secondary form of diabetes caused by pancreatic disease, such as chronic pancreatitis, that impairs insulin and glucagon secretion and results in poor glycemic control. Often misdiagnosed as type 2 diabetes, this pancreatic diabetes requires specific management due to elevated hemoglobin A1c levels, early insulin requirements, and increased risk of hypoglycemia. This case report discusses a 24-year-old man with hereditary chronic pancreatitis associated with the PRSS1 mutation, without typical symp­toms of exocrine pancreatic insufficiency, who presented with early insulin therapy and increased glycemic variability. The complexity of diagnosing this type of diabetes highlights the importance of diabetes screening in patients with chronic pancreatitis and the risk of inappropriate diagnosis and medical treatment.

Detection of Pancreatic Cancer and Nutritional Support in Chronic Pancreatitis

Chronic pancreatitis (CP) is a significant risk factor for pancreatic cancer and there had been a great deal of interest in surveillance and detection of pancreatic cancer. According to presence of genetic mutation, CP can be classified into hereditary CP and sporadic CP. CP with PRSS1 gene mutation showed a high incidence of pancreatic cancer justifying screening and surveillance for those older than 40 years. But CP with other mutations and sporadic CP have relatively low incidence of pancreatic cancer and surveillance is not recommended. While computed tomography or magnetic resonance imaging is widely used for screening, endoscopic ultrasound is not recommended because of parenchymal inflammation, fibrosis, and calcification associated with CP. However, when a patient with CP has multiple risk factors for pancreatic cancer, risk of pancreatic cancer increases significantly. Patients with CP have increased risk of pancreatic cancer at five years after diagnosis; individualized screening and surveillance based on symptoms and specific circumstances should be considered. Patients with CP have a high risk of malnutrition and malnutrition is quite common. Clinicians should assess nutritional status and implement nutritional support. Nutritional support must include both macronutrients and micronutrients. Given the high risk of osteoporosis and osteopathy in CP, clinicians should consider early diagnosis, prevention, and treatment. Consultation with nutritional support team is highly recommended.

Point-shear wave elastography generated by acoustic radiation force impulse in chronic pancreatitis.

Transcutaneous point-shear wave elastography (p-SWE) performed using an acoustic radiation force impulse can be used to quantify pancreatic stiffness in chronic pancreatitis (CP). We aimed to evaluate its usefulness to diagnose and monitor CP. 175 participants were included in this prospective study including patients with CP (n=65), liver cirrhosis (LC; n=60), alcohol abuse (n=10) and healthy controls (n=40). Point-shear wave elastography of the pancreas was performed and quantified as median shear wave velocity (SWV). In the same way, p-SWE of the spleen served as a marker of portal hypertension. The M-ANNHEIM Severity score was used as global marker for disease activity in CP. Compared to healthy controls, pancreatic SWV was significantly elevated in CP (1.38 vs. 0.96m/s; p<0.0001, MWU-test). Pancreatic SWV was increased in alcoholic CP but not in hereditary CP. Receiver operating characteristic analysis revealed 1.2m/s as the optimal cut-off to identify non-heredity-CP subjects (90% specificity; 81% sensitivity; 92% positive predictive value). Pancreatic SWV correlated significantly with the M-ANNHEIM Severity score, severity of CP-typical complications (both p<0.05, linear regression analysis), morphological changes of the pancreas and need for hospital treatment (both p<0.05, MWU-test) but not with exocrine or endocrine insufficiency. Pancreatic SWV >1.7m/s was identified to predict M-ANNHEIM Severity score ≥11 points. Pancreatic SWV was also elevated in LC (1.42m/s; p<0.001), correlating with increased splenic SWV. Transcutaneous pancreatic p-SWE represents a bedside, cost-effective and non-invasive tool which adds valuable information to the process of diagnosing and monitoring CP. By portal hypertension, an increased pancreatic SWV must be expected.

Clinical and Genetic Description of Hereditary Chronic Pancreatitis in Pakistani Children.

The purpose of this study was to identify the spectrum and frequency of pathogenic variants as well as the clinical and genetic insight of hereditary chronic pancreatitis in Pakistani children. The deoxyribonucleic acid of affected probands of 44 unrelated Pakistani families, having hereditary chronic pancreatitis-affected children, were subjected to massive parallel sequencing for candidate reported genes (SPINK1, PRSS1, CFTR, CPA1, CTRC, CBS, AGL, PHKB, and LPL). Data were analyzed using different bioinformatics tools for the variants and in-silico analysis. All the identified variants were validated by direct sequencing of the targeted exons in the probands and their parents. There were 50 patients included in this study with confirmed hereditary chronic pancreatitis. Nine known mutations in SPINK1, PRSS1, CFTR, CTRC, CBS, and AGL genes, and 10 novel variants in LPL, CFTR, CTR, and PHKB genes were identified. The identified variants were found in heterozygous, compound heterozygous, and trans-heterozygous forms, with rare allele frequency in the normal population. The novel variants were [c.378C>T(p.Lys126Asn) and c.719G>A(p.Arg240Gln) in CTRC, c.586-3C>A and c.763A>G(p.Arg255Gly) in CPA1, c.1160_1161insT(p.Lys387Asnfs*26), c.784C>T(p.Gln262*), c.1139+1G>A, c.175G>A(p.Gly59Arg) in LPL, c.388C>G(p.leu130val) in CFTR, and c.2327G>A(p.Arg776His in PHKB)]. The phenotypic characteristics were variable and correlated with the relevant variant. The genetic composition plays a significant role in the predisposition of hereditary chronic pancreatitis. The clinical presentation varies with the genetic determinant involved. This information would help in building up a diagnostic algorithm for our population that can be used for genetic screening services in affected cohorts.

Frey procedure for hereditary chronic pancreatitis in pediatric sibling.

Frey procedure for hereditary chronic pancreatitis in pediatric sibling.

Rate of Autoactivation Determines Pancreatitis Phenotype in Trypsinogen Mutant Mice

The digestive protease trypsin plays a central role in the onset and progression of pancreatitis. 1 Hegyi E. et al. Dig Dis Sci. 2017; 62: 1692-1701 Crossref PubMed Scopus (100) Google Scholar Ectopic conversion of the inactive precursor trypsinogen to active trypsin in the pancreas is an early event in disease development. Biochemically, trypsinogen is activated by limited proteolysis of its activation peptide, which can be cleaved by 3 different enzymes: enteropeptidase (enterokinase), trypsin (autoactivation), and cathepsin B (CTSB) (Figure 1A). Because enteropeptidase is not expressed in the pancreas, pathologic intrapancreatic trypsinogen activation can only occur through autoactivation or by CTSB-mediated activation. Inborn mutations of human cationic trypsinogen (encoded by the serine protease 1, PRSS1, gene) accelerate trypsinogen autoactivation and cause hereditary chronic pancreatitis (CP). 2 Mayerle J. et al. Gastroenterology. 2019; 156: 1951-1968 Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar In contrast, human genetic studies and functional analysis of trypsinogen mutants failed to substantiate a pathogenic role for CTSB-mediated trypsinogen activation in CP (references in Demcsák et al 3 Demcsák A. et al. Sci Rep. 2019; 9: 9188 Crossref PubMed Scopus (5) Google Scholar ).

EP261: The spectrum of CFTR and PRSS1 pathogenic variants in chronic pancreatitis

Chronic pancreatitis is defined as persistent inflammation of the pancreas that is ongoing for 6 months or longer. Chronic pancreatitis often develops by early adulthood in affected individuals and can lead to permanent tissue damage and loss of pancreatic function, including both exocrine and endocrine pancreatic insufficiency. Chronic pancreatitis increases the risk for diabetes and pancreatic cancer, more so with smoking and use of alcohol. Variants in several genes have been identified to be causative for, or induce susceptibility to, chronic pancreatitis. Genetic testing for hereditary chronic pancreatitis can aid in differential diagnosis of chronic pancreatitis from other disorders which also present with pancreatitis and may inform treatment strategy. This study reports the spectrum of pathogenic variants in individuals referred for chronic pancreatitis panel testing. This study included 747 individuals who underwent chronic pancreatitis panel testing at a single clinical laboratory (PreventionGenetics) between June 15, 2018 and September 24, 2021. Clinical information was obtained from provider-completed test requisition forms. Next generation sequencing (NGS) with copy number variant (CNV) detection was performed on patient-derived DNA using the Illumina NovaSeq 6000 platform (Illumina, San Diego, CA, USA) and Sanger sequencing as necessary. Testing provided 100% coverage for the coding regions of the CASR, CFTR, CTRC, PRSS1, and SPINK1 genes plus ∼10 bases of non-coding DNA flanking each exon, as well as non-coding regions in which pathogenic variants had been identified by the clinical testing laboratory or reported elsewhere. The test also included sequencing of CFTR regions within intron 11 and intron 21, along with a complete analysis of the compound (TG)n(T)n sequence (5T/TG tract) in intron 8. Variations in the 5T/TG tract have been reported to cause congenital absence of the vas deferens, non-classic cystic fibrosis, and classic cystic fibrosis. At time of testing, the patients ranged in age from 1 week to 87 years, with a median age of 32 years. Of the patients tested, 68% were negative for variants in genes included on the panel that are likely to cause disease while 27% were found to be indeterminate, where variants were identified but the results were not diagnostic. Overall, 5% of patients were positive, with a clear molecular diagnosis identified. Pathogenic and likely pathogenic variants in CFTR and PRSS1 accounted for 90% of positive cases overall, with 42% of positive cases being attributed to CFTR-related pancreatitis (1 homozygous or 2 heterozygous causative variants identified) and 33% of positive cases attributed to PRSS1-related pancreatitis (1 heterozygous causative variant). An additional 15% of positive cases were found to have pathogenic or likely pathogenic variants in both CFTR and PRSS1 (1 heterozygous causative variant in both CFTR and PRSS1). The CFTR c.1210-34TG[12]T[5] variant (more commonly referred to as 5T/12TG) contributed to ∼21% of CFTR-related pancreatitis. Importantly, ∼72% of pathogenic and likely pathogenic variants identified in this patient cohort are approved as therapy responsive variants for FDA approved CFTR modulators. In approximately 40% of patients with PRSS1-related pancreatitis, we detected a ∼600kb copy number gain encompassing the whole PRSS1 gene, compared to an estimated 6% of patients in the literature. These data indicate that variants in CFTR are a common cause of chronic pancreatitis and highlights the clinic utility of including complete analysis of the compound (TG)n(T)n sequence (5T/TG tract) in intron 8 of CFTR in this patient cohort. Additionally, the high frequency of treatment responsive variants suggests that a molecular diagnosis in patients with chronic pancreatitis may alter treatment strategy, particularly in the context of CFTR-related pancreatitis. Furthermore, these data suggest that whole gene deletions/duplications may be more frequent that previously thought in this patient cohort and that complex copy number variants in the PRSS1 gene may escape detection by other NGS testing strategies.

Chronic progression of cerulein-induced acute pancreatitis in trypsinogen mutant mice

T7K24R mice carry mutation p.K24R in mouse cationic trypsinogen (isoform T7), which is analogous to the human hereditary pancreatitis-associated mutation p.K23R. The mutation renders trypsinogen more prone to autoactivation. We recently reported that T7K24R mice exhibit increased severity of acute pancreatitis induced by repeated cerulein injections. The objective of the present study was to test whether trypsinogen mutant mice are prone to develop chronic pancreatitis, as observed in patients. We characterized the natural course of cerulein-induced pancreatitis in T7K24R mice and the C57BL/6N parent strain from the acute episode to 3 months post-attack. As expected, an acute episode of pancreatitis in C57BL/6N mice was followed by rapid recovery and histological restitution. In stark contrast, T7K24R mice developed progressive chronic pancreatitis with acinar cell atrophy, persistent macrophage infiltration, and diffuse fibrosis. The nadir of pancreas damage occurred on days 5–6 after the acute episode and was accompanied by digestive dysfunction. Remarkably, histological recovery was markedly delayed and permanent, chronic changes were still detectable 1–3 months after the acute pancreatitis episode. We conclude that during cerulein-induced acute pancreatitis in T7K24R mice, trypsin triggers an autonomous inflammatory program resulting in chronic disease progression, even after the cessation of cerulein-mediated injury. We propose that this uniquely trypsin-dependent mechanism explains the development of hereditary chronic pancreatitis in humans. Trypsin inhibition during acute attacks should prevent or delay progression to chronic disease.

Functionally deficient TRPV6 variants contribute to hereditary and familial chronic pancreatitis.

The recent discovery of TRPV6 as a pancreatitis susceptibility gene served to identify a novel mechanism of chronic pancreatitis (CP) due to Ca2+ dysregulation. Herein, we analyzed TRPV6 in 81 probands with hereditary CP (HCP), 204 probands with familial CP (FCP), and 462 patients with idiopathic CP (ICP) by targeted next-generation sequencing. We identified 25 rare nonsynonymous TRPV6 variants, 18 of which had not been previously reported. All 18 variants were characterized by a Ca2+ imaging assay, with 8 being identified as functionally deficient. Evaluation of functionally deficient variants in the three CP cohorts revealed two novel findings: (i) functionally deficient TRPV6 variants appear to occur more frequently in HCP/FCP patients than in ICP patients (3.2% vs. 1.5%) and (ii) functionally deficient TRPV6 variants found in HCP and FCP probands appear to be more frequently coinherited with known risk variants in SPINK1, CTRC, and/or CFTR than those found in ICP patients (66.7% vs 28.6%). Additionally, genetic analysis of available HCP and FCP family members revealed complex patterns of inheritance in some families. Our findings confirm that functionally deficient TRPV6 variants represent an important contributor to CP. Importantly, functionally deficient TRPV6 variants account for a significant proportion of cases of HCP/FCP.

Lived Experience of Hereditary Chronic Pancreatitis - A Qualitative Interview Study.

Hereditary chronic pancreatitis is a rare condition characterized by intermittent acute episodes of pancreatitis and long-term impairment of pancreatic functions. However, the subjective perspective of individuals affected by hereditary chronic pancreatitis has been little studied. This qualitative study investigates the experience of hereditary chronic pancreatitis patients and their relatives because the awareness of the needs of those affected is an essential component of a patient-centered management of chronic conditions. Semi-structured qualitative interviews were conducted with hereditary chronic pancreatitis patients and their relatives. Data were analysed using qualitative content analysis. The concepts of 'biographical contingency,' 'biographical disruption' and the 'shifting perspectives model' served as theoretical frameworks. A total of 24 participants (17 patients, 7 relatives) were interviewed individually. Four main themes were identified: (1) The unpredictable clinical course of hereditary chronic pancreatitis; (2) hereditary chronic pancreatitis as a devastating experience; (3) hereditary chronic pancreatitis as part of a normal life; and (4) being reduced to hereditary chronic pancreatitis. The 'shifting perspectives model' of chronic illness covers the four dimensions adequately and can serve as a theoretical model to explain hereditary chronic pancreatitis patients' experience. A better understanding of the patients and their families' experience and the shifting character of hereditary chronic pancreatitis can help healthcare professionals to tailor the care to meet the needs of those affected.

Perceptions of genetic testing in patients with hereditary chronic pancreatitis and their families: a qualitative triangulation

Hereditary chronic pancreatitis (HCP) is a genetically determined condition characterized by intermittent acute episodes of pancreatitis and long-term impairment of the exocrine and endocrine pancreatic functions. Genetic test results can have substantial psychological and social consequences for the individuals tested and their families. Nevertheless, little is known so far about the subjective experience of individuals genetically tested for HCP. This qualitative study examines the viewpoints of HCP patients and their relatives in order to identify the psychosocial and ethical implications related to genetic testing within families. Semi-structured qualitative individual interviews and a focus group with HCP patients and their family members were conducted. Data were audio-recorded, transcribed verbatim and analysed using qualitative content analysis. A total of 28 individuals were enrolled in the study: 24 individuals (17 patients, 7 relatives) were interviewed in semi-structured one-on-one interviews and 4 individuals (2 patients, 2 life partners) participated in the focus group. Emerging topics covered (1) genetic testing in childhood, (2) genetic testing within the family and (3) family planning. The study reveals that genetic testing for HCP has a wide influence in familial contexts and is accompanied by normative issues, such as autonomy, reproductive decisions and sharing of information within the family. The results raise the awareness of the complexity of family contexts: familial relationships and dynamics can have great influence on the individual decisions related to genetic testing. Increased understanding of these relational contexts can help health professionals, for example, in counselling, to discuss genetic testing better with patients and families.

Duodenal-preserving pancreatic head resection with limited distal pancreatectomy: A novel, tailored approach for chronic pancreatitis

Presenter: Thomas Maatman MD | Indiana University Background: Operative management of chronic pancreatitis (CP) must be tailored to individual patient’s anatomy to achieve durable symptom relief. Incomplete drainage of an atrophic pancreatic tail is a common cause of symptom recurrence in patients undergoing drainage procedures. We have selectively applied limited distal pancreatectomy (DP) with duodenal-preserving pancreatic head resection (DPPHR) to patients with appropriate anatomy and hypothesized that this novel procedure provides durable therapy. Methods: Ten patients underwent DPPHR combined with limited DP between 2013-2018. Patient demographics, comorbidities, perioperative outcomes, and long-term CP-specific outcomes were recorded. Measurements of the pathology specimen determined pancreas tail volume. Chronic pancreatitis specific outcomes included endocrine/exocrine insufficiency, pain relief, and nutritional status. The amount of opioid pain medication was reported as daily morphine equivalents. Body mass index (BMI) and albumin were reported as surrogates for nutritional status. Descriptive statistics were applied. Continuous data are reported as means ± standard error of the mean. Results: Ten patients (8 females; age 49 ± 3 years) had etiology of idiopathic (n = 4), alcohol (n = 2), sequelae of severe acute pancreatitis (n = 1), hereditary (n = 1), autoimmune (n = 1), and pancreas divisum (n = 1). Operation was 57 ± 14 months after CP diagnosis. Patients had 6 ± 1 endoscopic procedures prior to operation. Mean operative time was 215 ± 11 minutes; estimated blood loss was 110 ± 28 mL. On average, 6 ± 1 cm of pancreatic tail was resected. Splenic preservation was possible in 7 patients. Postoperative LOS was 13 ± 2 days. Postoperative morbidity occurred in two patients; one grade B postoperative pancreatic fistula and one perforated duodenal ulcer. Readmission occurred in 5/10 patients at median time of 36 days (range, 16-78 days) postoperatively. Causes included abdominal pain (n = 2), small bowel obstruction (n = 1), intraabdominal abscess requiring antibiotic therapy (n = 1), and failure to thrive (n = 1). No perioperative mortality occurred. Overall, analgesic requirements and nutrition (measured by albumin) improved substantially (Figure 1). In addition, improvement in BMI (preoperative, 23.5 ± 1 kg/m2) was sustained at one- (23.7 ± 1 kg/m2), three- (25.6 ± 1 kg/m2), and five-years postoperatively (24.2 ± 1 kg/m2). At operation, 20% of patients required insulin; at five-year follow up this number was 25%. Eighty percent of patients were prescribed exocrine replacement preoperatively; all patients were on exocrine replacement at five-year follow up. During follow up (mean, 38 ± 7 months), one patient with hereditary CP underwent salvage total pancreatectomy with islet cell auto-transplantation 13 months postoperatively. Conclusion: In select chronic pancreatitis patients, including limited distal pancreatectomy with duodenal-preserving pancreatic head resection provides durable, long-term pain relief and improves nutritional parameters with minimal effect on pancreatic endocrine and exocrine function. This operation should be considered in select patients with appropriate anatomy.

Chronic pancreatitis as a risk factor for pancreatic cancer (a clinical case)

The differential diagnosis between chronic pancreatitis (CP) and pancreatic cancer (PC) is a challenging issue in the clinical practice, taking into account common risk factors shared by these disorders (smoking, obesity, diabetes mellitus and insulin resistance), as well as a high risk of PC development against the underlying CP of 2 to 3 years' duration; this risk would be manifold in hereditary CP. The article presents a clinical case of PC in a 60-year old man at three years after he had been diagnosed with CP. The disease manifested from an acute episode of pancreatitis, which was treated in a hospital. Two years later, the patient suffered from acute destructive pancreatitis complicated by portal vein thrombosis and formation of pseudocysts. Subsequently, there was a rupture of the post-necrotic cyst with leakage into the abdominal cavity; this required surgical intervention. The differential diagnosis between CP and PC was done at all steps of the diagnostic work-up and treatment. However, after the inflammation resolved, there was a period of apparent well-being, during which the patient developed PC. This clinical case is intended to draw attention of clinicians, while making differential diagnosis, to the detailed past history assessment, use of multiaxial computed tomography with intravenous bolus contrast enhancement, and endoscopic ultrasound examination with elastography. In difficult cases, regular follow-up of at least every three months would be necessary.

Australian Experience of Total Pancreatectomy and Islet Auto Transplant (TPIAT) Utilizing a Remote Isolation Center

Introduction In 2015 we performed the first TPIAT in Australia on a 7 year old paediatric patient suffering hereditary chronic pancreatitis due to a PRSS1 mutation. We have since performed a further 4 TPIAT procedures, 2 paediatric and 2 adult recipients. All 5 TPIAT procedures were performed in Adelaide, South Australia at the Women’s and Children’s Hospital (paediatric patients) or the Royal Adelaide Hospital (adult patients). The islet isolation procedure was performed at a remote isolation center, St Vincent’s Institute (SVI), Melbourne Victoria. SVI is a 1hr15min commercial flight from Adelaide or approximately 470 miles by road. Following isolation, the islets were infused back into each patient on the same day in Adelaide. Materials and Methods In the first 2 patients a total pancreatectomy, splenectomy, cholecystectomy, and biliary and enteric reconstruction was performed. In patients 3-5 the spleen was spared during the total pancreatectomy. Once removed, the pancreas was placed in preservation solution and escorted from Adelaide to Melbourne by commercial airline. Pancreatic digestion and islet isolation were performed using Serva enzyme and standard protocols. Islet infusion into the liver was performed by cannulation of the portal vein with concomitant portal vein pressure monitoring. Results The cold ischaemic time for all 5 pancreas was similar, ranging from 5hr to 5hr21min. The pancreas weights varied significantly, however this did not correlate with islet yield. Total IEQ ranged from 28,254 to 653,222 and the time from placing the islets into transplant bags through to infusion into the recipient was relatively consistent, ranging from 4-5hrs. To date, patients 1 & 3 have ceased all pre-operative pain medication and patient 4 has significantly reduced his opiate usage and is currently undergoing a controlled withdrawal and detoxification program with medical guidance to cease the remaining analgesia. Patient 5 the most recent TPIAT is in the process of weaning off her pre-operative analgesia and patient 2 suffered complications following TPIAT and is deceased. All 4 surviving patients are c-peptide positive with daily insulin requirements ranging from 10-20U and HbA1c levels of 5-8. Conclusion We have successfully completed a pilot study involving 5 patients undergoing TPIAT for the management of chronic pancreatitis. All 5 isolations were performed at a facility remote to the hospital where the total pancreatectomy and subsequent islet infusion was performed. All surviving recipients have experienced a reduction or complete resolution of their chronic pain following TPIAT with two patients no longer requiring any form of analgesia. They are all c-peptide positive, requiring minimal doses of exogenous insulin with excellent management of their diabetes. Recently, we secured additional funding to perform 6 more TPIATs with the long-term goal of establishing TPIAT as a government funded procedure for the treatment of chronic pancreatitis. The Hospital Research Foundation South Australia. MedVet Sciences South Australia. Women’s and Children’s Hospital.

Hereditary chronic pancreatitis in a patient with type 1 diabetes mellitus

In this case report, we present a young patient with type 1 diabetes who had hereditary chronic pancreatitis. We evaluated him for the cause of pancreatitis, but it was inconclusive and finally the genetic testing was done for him, which revealed heterozygous missense mutation in exon 3 of the PRSS1 gene (protease serine 1 gene) on chromosome 7. Hence, we were able to make the diagnosis of hereditary chronic pancreatitis. Chronic pancreatitis secondary to any cause can lead to permanent diabetes, which is typically difficult to control. However, in this case, the episodes of recurrent pancreatitis were present after the onset of type 1 diabetes as compared to the usual presentation of diabetes after the advancement of chronic pancreatitis.

A novel p.Ser282Pro CPA1 variant is associated with autosomal dominant hereditary pancreatitis

We read with great interest the recent publication by Nemeth et al .1 in which the authors demonstrate that a misfolding human cationic trypsinogen (serine protease 1, PRSS1) variant causes autosomal dominant hereditary chronic pancreatitis (CP) by inducing endoplasmic reticulum (ER) stress. Previously, the same mechanism was proposed for carboxypeptidase A1 ( CPA1 ) gene variants strongly associated with early onset sporadic CP;2 however, the association of misfolding CPA1 variants with familial or hereditary CP has not been demonstrated so far. Here, we report two Polish families with hereditary CP carrying a novel heterozygous c.844T>C (p.Ser282Pro) CPA1 variant. In Family 1, the index patient, her mother and uncle (half-brother of the mother) developed CP (figure 1). The age of diagnosis was 17 years for the index patient and 51 and 31 years (with earlier abdominal pain) for the mother and the uncle, respectively. In Family 2, three members were affected by CP (figure 1): the index patient, her mother and her father with ages of onset of 12, 32 and 34 years, respectively. In both families, the diagnosis of CP was confirmed by …

CEL-HYB allele in Polish patients with hereditary or idiopathic chronic pancreatitis

CEL-HYB allele in Polish patients with hereditary or idiopathic chronic pancreatitis

The Differential Role of Human Cationic Trypsinogen (PRSS1) p.R122H Mutation in Hereditary and Nonhereditary Chronic Pancreatitis: A Systematic Review and Meta-Analysis.

Background Environmental factors and genetic mutations have been increasingly recognized as risk factors for chronic pancreatitis (CP). The PRSS1 p.R122H mutation was the first discovered to affect hereditary CP, with 80% penetrance. We performed here a systematic review and meta-analysis to evaluate the associations of PRSS1 p.R122H mutation with CP of diverse etiology. Methods The PubMed, EMBASE, and MEDLINE database were reviewed. The pooled odds ratio (OR) with 95% confidence intervals was used to evaluate the association of p.R122H mutation with CP. Initial analysis was conducted with all etiologies of CP, followed by a subgroup analysis for hereditary and nonhereditary CP, including alcoholic or idiopathic CP. Results A total of eight case-control studies (1733 cases and 2415 controls) were identified and included. Overall, PRSS1 p.R122H mutation was significantly associated with an increased risk of CP (OR = 4.78[1.13–20.20]). Further analysis showed p.R122H mutation strongly associated with the increased risk of hereditary CP (OR = 65.52[9.09–472.48]) but not with nonhereditary CP, both alcoholic and idiopathic CP. Conclusions Our study showing the differential role of p.R122H mutation in various etiologies of CP indicates that this complex disorder is likely influenced by multiple genetic factors as well as environmental factors.

Genetically Determined Chronic Pancreatitis but not Alcoholic Pancreatitis Is a Strong Risk Factor for Pancreatic Cancer.

To study if chronic pancreatitis (CP) is a risk factor for pancreatic cancer. Through a cohort and a case-control study design, CP and other important risk factors including smoking, diabetes, alcohol, obesity, and genetic mutations were studied for their association with pancreatic cancer. In the cohort study, 402 patients with CP were included. During 3967.74 person-years of exposure, 5 of the 402 patients (4 idiopathic CP, 1 hereditary CP) developed pancreatic cancer after 16.60 ± 3.51 years of CP. The standardized incidence ratio was 121. In the case-control study, 249 pancreatic cancer patients and 1000 healthy controls were included. Of the 249 patients with pancreatic cancer, 24 had underlying idiopathic CP, and none had alcoholic pancreatitis. SPINK1 gene mutation was present in 16 of 26 patients with idiopathic CP who had pancreatic cancer. Multivariable analysis showed CP (odds ratio [OR], 97.67; 95% confidence interval [CI], 12.69-751.36), diabetes (>4 years duration) (OR, 3.05; 95% CI, 1.79-5.18), smoking (OR, 1.93; 95% CI, 1.38-2.69) as significant risk factors for pancreatic cancer. The population attributable risk was 9.41, 9.06, and 9.50 for diabetes, CP, and smoking, respectively. Genetically determined CP but not alcoholic CP is a strong risk factor for pancreatic cancer.