Characterization of novel PNLIP variants in congenital pancreatic lipase deficiency.

BACKGROUND/OBJECTIVES: Studies of a rare homozygous missense mutation identified in two brothers diagnosed with congenital pancreatic lipase deficiency (CPLD) provided the first definitive evidence linking CPLD with missense mutations in the gene of PNLIP. Herein, we investigated the molecular basis for the loss-of-function in the three novel PNLIP variants (c.305G > A, p.(W102∗); c.562C > T, p.(R188C); and c.1257G > A, p.(W419∗)) associated with CPLD. METHODS: We characterized three novel PNLIP variants in transfected cells by assessing their secretion, intracellular distribution, and markers of endoplasmic reticulum (ER) stress. RESULTS: All three variants had secretion defects. Notably, the p.R188C and p.W419∗ variants induced misfolding of PNLIP and accumulated as detergent-insoluble aggregates resulting in elevated BiP at both protein and mRNA levels indicating increased ER stress. CONCLUSIONS: All three novel PNLIP variants cause a loss-of-function through impaired secretion. Additionally, the p.R188C and p.W419∗ variants may induce proteotoxicity through misfolding and potentially increase the risk for pancreatic acinar cell injury.

The role of asparagine synthetase on nutrient metabolism in pancreatic disease.

The pancreas avidly takes up and synthesizes the amino acid asparagine (Asn), in part, to maintain an active translational machinery that requires incorporation of the amino acid. The de novo synthesis of Asn in the pancreas occurs through the enzyme asparagine synthetase (ASNS). The pancreas has the highest expression of ASNS of any organ, and it can further upregulate ASNS expression in the setting of amino acid depletion. ASNS expression is driven by an intricate feedback network within the integrated stress response (ISR), which includes the amino acid response (AAR) and the unfolded protein response (UPR). Asparaginase is a cancer chemotherapeutic drug that depletes plasma Asn. However, asparaginase-associated pancreatitis (AAP) is a major medical problem and could be related to pancreatic Asn depletion. In this review, we will provide an overview of ASNS and then describe its role in pancreatic health and in the exocrine disorders of pancreatitis and pancreatic cancer. We will offer the overarching perspective that a high abundance of ASNS expression is hardwired in the exocrine pancreas to buffer the high demands of Asn for pancreatic digestive enzyme protein synthesis, that perturbations in the ability to express or upregulate ASNS could tip the balance towards pancreatitis, and that pancreatic cancers exploit ASNS to gain a metabolic survival advantage.

Report on the Short Endoscopic Exocrine Pancreatic Function Test in Children and Young Adults.

OBJECTIVES: Endoscopic pancreatic function test (ePFT) has been in use for exocrine function testing since the 1990s. In patients, short ePFT assesses acinar function, unlike the longer version for ductal function in adults. The present study summarizes characteristics of 1913 short ePFTs (S-ePFT) performed at 2 centers since 2001. METHODS: The main indications in patients presenting at ages infancy to 24.3 years, for the S-ePFT were failure to thrive, weight loss, diarrhea, and abdominal pain with bloating. Secretin was administered as bolus, and 4 aliquots of fluid were collected between 4 and 10 minutes after administration. Amylase, lipase, trypsin, and chymotrypsin activities were measured in the laboratory. RESULTS: The pH of consecutive samples increased by 0.3 to 0.7. Overall, 36.7% had abnormal S-ePFT with selective amylase deficiency (9.5%) and generalized enzyme deficiency (8.9%) being the most frequent. Retest reproducibility, repeatability, and clinical validity were high. By adding S-ePFT to endoscopy for the suspicion of malabsorption, the abnormal findings increased by 36.9%. CONCLUSIONS: Short ePFT assesses pancreatic acinar function in a reliable and clinically meaningful way in patients. Diagnostic yield of endoscopy increased substantially albeit with increased sedation time. By S-ePFT ductal function, cytokines and proteomics can also be assessed.

Benign Pancreatic Hyperenzymemia, Also Known as Gullo's Syndrome.

Benign pancreatic hyperenzymemia, also known as Gullo's syndrome, is a little-known syndrome first described in 1996 in patients studied for an elevation of pancreatic enzymes while otherwise being asymptomatic. We describe the case of a 2-year-old patient who was found to have significant elevation of amylase and lipase levels while he was asymptomatic. Blood tests and imaging tests were performed to determine the etiology, but they gave normal results. The enzyme elevation can even be 10 times the normal value of the enzyme, and only 1 enzyme may elevate, although most often all pancreatic enzymes are elevated. The etiology is not known, although several hypotheses have been suggested. This enzyme elevation is described both in adults and children and also sporadically or with a familial pattern. Knowledge of it can limit the performance of the multiple complementary test, some of which are very invasive in patients who have elevated pancreatic enzymes while they are asymptomatic. It knowledge allows us to confirm a benign prognosis about it and reassure the family about this disease and that in the end it will not require aggressive treatments such as surgery or chemotherapy.

Chronic Asymptomatic Pancreatic Hyperenzymemia: A Long-term Follow-up.

OBJECTIVES: Chronic asymptomatic pancreatic hyperenzymemia (CAPH) was described as a benign disease. However, we already described clinically relevant findings requiring surgery or follow-up in half of the subjects. The aim of this study was to evaluate the long-term outcome of CAPH in terms of symptoms and evolution toward chronic pancreatitis. METHODS: Subjects previously enrolled in the first phase of the study (from 2005 to 2010) were reinvestigated from December 2013 to January 2017 with a phone call ± magnetic resonance cholangiopancreatography with secretin stimulation. RESULTS: A total of 133 subjects were eligible for the follow-up study (75 males, 58 females; age, 48.4 [standard deviation {SD}, 14] years); 24 (18%) of them dropped out. During a mean follow-up of 9.3 (SD, 5.2) years after the first diagnosis of CAPH, no episode of acute pancreatitis or abdominal pain was reported. Sixty-three subjects (58%) of 109 underwent magnetic resonance cholangiopancreatography with secretin stimulation with a mean follow-up of 5.7 [SD, 3.1] years (range, 1-11 years). Secretin stimulation-MRCP resulted unchanged in 54 (90%) of 60 subjects, worsened in 3 (5%) and improved in 3 (5%). Two subjects died from causes unrelated to pancreatic disease. CONCLUSIONS: Excluding subjects with a pancreatic disease at index magnetic resonance imaging, CAPH is a benign condition.

Association between chronic asymptomatic pancreatic hyperenzymemia and pancreatic ductal anomalies: a magnetic resonance cholangiopancreatography study.

PURPOSE: Elucidating the association between pancreatic ductal anomalies and chronic asymptomatic pancreatic hyperenzymemia using magnetic resonance cholangiopancreatography. METHODS: We conducted a single-center, retrospective, case-control study. The healthy community group comprised 554 subjects who participated in a paid, whole-body health checkup program. The patient group comprised 14 subjects with idiopathic pancreatic hyperamylasemia or hyperlipasemia. All subjects underwent magnetic resonance cholangiopancreatography. The clinical features and incidence rates of pancreatic ductal anomalies were then compared between the groups. RESULTS: Compared to the healthy community group, the patient group was significantly more likely to be ≥ age 65 (71.4% of patient group vs. 22.1% of healthy community group), have a history of diabetes mellitus (21.4% vs. 5.4%) or hypertension (35.7% vs. 11.4%), and to have pancreas divisum (21.4% vs. 2.7%), meandering main pancreatic duct (21.4% vs. 4.1%), Wirsungocele (14.3% vs. 1.1%), or dilated main pancreatic duct (14.3% vs. 2.3%). Multivariate analysis found that age ≥ 65 (odds ratio 8.76), presence of pancreas divisum (odds ratio 13.2), meandering main pancreatic duct (odds ratio 8.95), and Wirsungocele (odds ratio 17.6) were independent factors significantly associated with chronic asymptomatic pancreatic hyperenzymemia. CONCLUSIONS: Pancreas divisum, meandering main pancreatic duct, and Wirsungocele were independently associated with chronic asymptomatic pancreatic hyperenzymemia.

Man with epigastric pain and persistently elevated serum lipase.

Serum lipase and amylase are commonly requested in individuals presenting with abdominal pain for investigation of acute pancreatitis. Pancreatic hyperenzymaemia is not specific for acute pancreatitis, occurring in many other pancreatic and non-pancreatic conditions. Where persistent elevation of serum lipase and amylase occurs in the absence of a diagnosed cause or evidence of laboratory assay interference, ongoing radiological assessment for pancreatic disease is required for 24 months before a diagnosis of benign pancreatic hyperenzymaemia can be made. We report a case of a 71-year-old man with epigastric pain and elevated serum lipase levels. He was extensively investigated, but no pancreatic disease was detected. He is asymptomatic, but serum lipase levels remain elevated 18 months after his initial presentation.

Chronic Asymptomatic Pancreatic Hyperenzymemia (CAPH): Meta-analysis of pancreatic findings at second-level imaging.

BACKGROUND/OBJECTIVES: Data estimating the prevalence of significant findings during the investigation of patients with Chronic Asymptomatic Pancreatic Hyperenzymemia (CAPH) are scanty and heterogeneous, and the diagnostic approach is therefore uncertain. The aim of this study was to meta-analyze pancreatic abnormalities detected at second-level imaging in patients with CAPH. METHODS: Pubmed database was searched until September 2018 for articles evaluating CAPH patients through MRI-Cholangio-Pancreatography with/without secretin (MRCP or s-MRCP) or Endoscopic Ultrasound (EUS). The methodology was developed from PRISMA checklist. Pooled prevalences of pancreatic findings were calculated, with subgroup analyses according to imaging modality. Quality of the studies, publication bias and heterogeneity were analyzed. RESULTS: In 8 articles describing 521 patients with CAPH, pooled prevalence of normal imaging was 56.6% [95%CI (CI) 41.9-70.2; I2 = 88.6%). Prevalences of neoplasia, chronic pancreatitis, pancreatic cysts and benign abnormalities were 2.2% [CI1.2-4.1; I2 = 0%], 16.2% [CI10.2-24.8; I2 = 71.5%], 12.8% [CI8.2-19.3; I2 = 64.7%] and 17.2% [CI11.9-24.2; I2 = 71.5%] respectively. In sub-analyses, EUS and s-CPRM were less frequently normal and diagnosed more "early" chronic pancreatitis, while neoplastic lesions were still rare. CONCLUSIONS: In CAPH patients, second-level pancreatic imaging is normal in 56% of the cases, neoplastic lesions are rare and the rate of pancreatic cysts is similar to that seen as incidental findings. More than one third of patients are diagnosed with abnormalities whose prognostic significance is uncertain. Despite the superior sensitivity of EUS or s-CPRM, the less costly/invasive and more available contrast-enhanced MRCP does not seem to miss relevant findings in this setting.

Can pancreatic steatosis affect exocrine functions of pancreas?

BACKGROUND/AIMS: Pancreatic steatosis (PS) is a generally used term to define accumulation of fat in the pancreas. In theory PS may be able to affect the exocrine function of pancreas. In this study we aimed to determine the effect of PS on exocrine pancreas function. MATERIALS AND METHODS: Forty-three patients with PS determined by 3 tesla magnetic resonance imaging (MRI) and 48 patients without PS were included in this study. Patients with PS were classified as group 1 and control patients were classified as group 2. Fecal elastase-1 levels were determined. Fecal elastase-1 levels <200 µg/g were defined as exocrine pancreatic insufficiency (EPI). Patients with PS were further grouped according to severity and anatomic distribution of steatosis based on findings of 3 tesla MRI. RESULTS: Fecal elastase-1 levels was significantly lower in group 1 compared to group 2 (319.76±45.7 vs 549.31±69.4, respectively, p=0.003). Proportion of patients with EPI was significantly higher in group 1 than group 2 (35.5% vs 12% p=0.042). There were no significant differences in terms of severity or the anatomic distribution of PS in patients with PS with EPI based on MRI (p=0.052, p=0.198, p=0.405) Conclusion: Current study demonstrates that PS can cause EPI.

Pancreatic panniculitis: the "bright" side of the moon in solid cancer patients.

BACKGROUND: Pancreatic panniculitis is a rare complication of pancreas disorders occurring in 0.3-3% of patients, most often accompanied by the pancreatic acinar carcinoma. It presents multiple, painful, deep, ill-defined, red-brown, migratory nodules and plaques of hard elastic consistency; often ulcerated and typically located on the lower proximal and distal extremities. The pathogenesis is not fully understood, but it is thought to result from lipolysis and fat necrosis with secondary tissue inflammation induced by pancreatic enzymes. Histopathology shows subcutaneous lobular fat necrosis with anuclear adipocytes (called ghost cells) surrounded by a mixed inflammatory infiltrate. Focal calcification may also be seen. The treatment is directed to the underlying disorder, which may result in regression of skin lesions. CASE PRESENTATION: We present two cases of pancreatic panniculitis with similar clinical, laboratory, and histopathological features associated with different internal malignancy. The first case, after extensive investigations showed the presence of a pancreatic carcinoma with multiple liver metastases and a poor prognosis. The second one instead is the first case in literature where painful subcutaneous nodules of the legs were the early manifestation of a neuroendocrine carcinoma of the adrenal gland. CONCLUSIONS: Although subcutaneous fat necrosis usually occurs late in the course of a malignancy, recognition of the association with pancreatic panniculitis may prevent a long delay in the diagnosis and management of the occult neoplasm. It should be primarily considered when panniculitis is widespread and persistent, and frequent relapses or tendency to ulcerate of the nodules are regarded as red flags.

The role of the carboxyl ester lipase (CEL) gene in pancreatic disease.

The enzyme carboxyl ester lipase (CEL), also known as bile salt-dependent or -stimulated lipase (BSDL, BSSL), hydrolyzes dietary fat, cholesteryl esters and fat-soluble vitamins in the duodenum. CEL is mainly expressed in pancreatic acinar cells and lactating mammary glands. The human CEL gene resides on chromosome 9q34.3 and contains a variable number of tandem repeats (VNTR) region that encodes a mucin-like protein tail. Although the number of normal repeats does not appear to significantly influence the risk for pancreatic disease, single-base pair deletions in the first VNTR repeat cause a syndrome of endocrine and exocrine dysfunction denoted MODY8. Hallmarks are low fecal elastase levels and pancreatic lipomatosis manifesting before the age of twenty, followed by development of diabetes and pancreatic cysts later in life. The mutant protein forms intracellular and extracellular aggregates, suggesting that MODY8 is a protein misfolding disease. Recently, a recombined allele between CEL and its pseudogene CELP was discovered. This allele (CEL-HYB) encodes a chimeric protein with impaired secretion increasing five-fold the risk for chronic pancreatitis. The CEL gene has proven to be exceptionally polymorphic due to copy number variants of the CEL-CELP locus and alterations involving the VNTR. Genome-wide association studies or deep sequencing cannot easily pick up this wealth of genetic variation. CEL is therefore an attractive candidate gene for further exploration of links to pancreatic disease.

Possible involvement of iNOS and TNF-α in nutritional intervention against nicotine-induced pancreatic islet cell damage.

Nicotine is the more abundant and most significant components of cigarette smoke. Epidemiological evidence strongly suggests an association between cigarette smoking and pancreatic injury. Although effects of smoking on endocrine pancreas are still controversial Here, we examined the impact and underlying mechanisms of action of folic acid and vitamin B12 on nicotine induced damage in pancreatic islets of rats. Male Wistar rats were treated with nicotine (3mg/kg body weight/day, intraperitonealy) with or without folic acid (36µg/kg body weight/day, orally) and vitamin B12 (0.63µg/kg body weight/day, orally) for 21days. Supplementation with folic acid and vitamin B12 suppressed the nicotine induced changes in HbA1c, insulin, TNF-α, IL-6, generation of reactive oxygen species, and attenuated the changes in markers of oxidative stress. Moreover, folic acid and vitamin B12 also counteracted the increased expression of protein and mRNA contents of TNF-α and iNOS produced by nicotine. Further, folic acid and vitamin B12 in combination limits the nicotine induced changes in cell cycle and excessive apoptosis of the pancreatic ß-cells and also successfully blunted the nicotine induced alteration in loss of mitochondrial membrane potential. In conclusion, data demonstrate that folic acid and vitamin B12 may be possible nutritional intervention against cellular oxidative stress, which is a critical step in nicotine-mediated islet injury, and improves islet cell functional status by scavenging free radicals and by inhibiting the generation of pro-inflammatory mediators.

Pancreatic morpho-functional imaging as a diagnostic approach for chronic asymptomatic pancreatic hyperenzymemia.

BACKGROUND: Magnetic resonance cholangio-pancreatography (MRCP) findings in people with chronic asymptomatic pancreatic hyperenzymemia (CAPH) have shifted the hypothesis that CAPH is always non-pathological. However, there have been no studies including both secretin-MRCP (S-MRCP) and endoscopic ultrasonography (EUS) to examine the pancreatic morphology in these subjects. AIM: To prospectively assess the diagnostic approach for CAPH using both pancreatic EUS and S-MRCP. METHODS: In a case-control prospective study from January 2010 to December 2014, 68 consecutive subjects with CAPH were scheduled to undergo S-MRCP and EUS (CAPH group) in a tertiary care setting. In the same period, the EUS findings of this group were compared with 68 patients examined by EUS alone for submucosal lesions of the gastric fundus, matched for sex and age (control group). RESULTS: EUS detected pancreatic alterations in 60.3% of the CAPH group and 13.2% of controls (p<0.001). S-MRCP showed pancreatic alterations in 51.5% in the CAPH group. With the combined procedures, pancreatic abnormalities were detected in 63.3%. The diagnoses established by the two techniques were concordant in 51 (75%) of the 68 CAPH subjects; in the remaining 17 (25%) the two methods gave additional information. CONCLUSIONS: In people with CAPH S-MRCP and EUS are both recommended in order to detect pancreatic abnormalities before this biochemical alteration is confirmed as benign CAPH, or Gullo's syndrome.

Healthy Chinese with benign pancreatic hyperenzymemia.

Benign pancreatic hyperenzymemia, or Gullo's syndrome, is an uncommon syndrome characterized by a long-term increase of serum pancreatic enzyme in the absence of pancreatic diseases. It is primarily discovered incidentally and occurs in either sporadic or familial form. Herein, we report the first case of benign pancreatic hyperenzymemia in Taiwan. A 57-year-old Chinese male was incidentally noted with elevated serum amylase and lipase levels during a health check-up and was diagnosed with benign pancreatic hyperenzymemia using a series of image and serological tests. Although this is the first case of benign pancreatic hyperenzymemia in Taiwan, its prevalence may be underestimated due to the diagnostic difficulties. Correct diagnosis of this disease is important to avoid costly test duplication, unfounded anxieties, and multiple consultations.

Quality of life in patients with long-standing chronic non-pathological pancreatic hyperenzymemia.

BACKGROUND: Chronic non-pathological pancreatic hyperenzymemia is a benign condition characterized by the persistent elevation of serum pancreatic enzymes without morphological alterations of the pancreas. No information is available regarding the quality of life of these subjects. AIM: To evaluate the physical, mental and psychological status of these subjects using SF-12 Health Survey questionnaire and the 12-item General Health Questionnaire. METHODS: Fifty-one consecutive subjects having long-standing chronic non-pathological pancreatic hyperenzymemia (duration: 11.0 years, range 5-21) were studied. The Italian version of the SF-12 questionnaire and the General Health Questionnaire were compiled by the subjects studied. RESULTS: Regarding the SF-12 questionnaire, the physical component scores and the mental component scores were 50.1 ± 8.0 and 44.7 ± 11.7, respectively and these figures were not statistically different from those of reference Italian population. Regarding the psychological status, seven subjects (13.7%) had non-psychotic-psychiatric problems. No statistical differences in the physical component score, mental component score and general health questionnaire were found between patients having non-familial or familial chronic non-pathological pancreatic hyperenzymemia. CONCLUSIONS: Subjects with long-standing chronic non-pathological pancreatic hyperenzymemia had a quality of life no different from that of the Italian population. The explanation provided by the physician regarding the benignity of long-standing chronic non-pathological pancreatic hyperenzymemia is enough to reassure this type of patient.

Serum enolase: a non-destructive biomarker of white skeletal myopathy during pancreas disease (PD) in Atlantic salmon Salmo salar L.

Diseases which cause skeletal muscle myopathy are some of the most economically damaging diseases in Atlantic salmon, Salmo salar L., aquaculture. Despite this, there are limited means of assessing fish health non-destructively. Previous investigation of the serum proteome of Atlantic salmon, Salmo salar L., during pancreas disease (PD) has identified proteins in serum that have potential as biomarkers of the disease. Amongst these proteins, the enzyme enolase was selected as the most viable for use as a biomarker of muscle myopathy associated with PD. Western blot and immunoassay (ELISA) validated enolase as a biomarker for PD, whilst immunohistochemistry identified white muscle as the source of enolase. Enolase was shown to be a specific marker for white muscle myopathy in salmon, rising in serum concentration significantly correlating with pathological damage to the tissue.

Pancreatic hyperenzymemia is associated with bacterial culture positivity, more severe and right-sided colitis.

BACKGROUND/AIM: Several studies reported pancreatic hyperenzymemia (PHE) related to acute colitis. However, there is no consensus on its clinical significance. This study was addressed to find the clinical significance of PHE in acute colitis. METHODS: Pancreatic hyperenzymemia was defined as abnormal increase in serum concentrations of the pancreatic enzymes by three times of normal upper range without definite pancreatic symptoms and evidence of pancreatitis at abdominal CT imaging of pancreatic disease. And clinical and laboratory and biologic parameters of PHE group and normal pancreatic enzymemia (NPE) group were compared. RESULTS: A total of 1,069 patients admitted to hospitals due to acute colitis were analyzed. Of these patients, 2.99 % (32/1,069) showed PHE. PHE group showed more severe symptoms and had longer hospital stays than the NPE group (12.15 vs. 4.59 days; P < 0.001). Multivariable analysis showed that right-sided colitis (OR 2.846; 95 % CI 1.122-7.224; P = 0.028) and culture positivity (OR 3.346; 95 % CI 1.119-10.008; P = 0.031) are associated with PHE during acute colitis. Also, PHE group was more common when a microorganism could be identified in the cultures (28.1 vs. 7.0 %; P = 0.003), especially blood culture. Among patients with positive cultures, Salmonella spp. had a positive correlation with the right-sided colitis and PHE (amylase P = 0.002; lipase P = 0.029), Salmonella serovar typhimurium (group B) was especially related to increased serum lipase but not to increased serum amylase (lipase; P = 0.041: amylase; P = 0.485). CONCLUSION: Pancreatic hyperenzymemia is associated with right-sided colitis, bacterial culture positivity, and severe acute colitis.