EUS pancreatic function testing and dynamic pancreatic duct evaluation for the diagnosis of exocrine pancreatic insufficiency and chronic pancreatitis

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Variants in the pancreatic CUB and zona pellucida-like domains 1 (CUZD1) gene in early-onset chronic pancreatitis - A possible new susceptibility gene

ObjectiveNon-alcoholic chronic pancreatitis (NACP) frequently develops in the setting of genetic susceptibility associated with alterations in genes that are highly expressed in the pancreas. However, the genetic basis of NACP remains unresolved in a significant number of patients warranting a search for further risk genes.DesignWe analyzed CUZD1, which encodes the CUB and zona pellucida-like domains 1 protein that is found in high levels in pancreatic acinar cells. We sequenced the coding region in 1163 European patients and 2018 European controls. In addition, we analyzed 297 patients and 1070 controls from Japan. We analyzed secretion of wild-type and mutant CUZD1 from transfected cells using Western blotting.ResultsIn the European cohort, we detected 30 non-synonymous variants. Using different prediction tools (SIFT, CADD, PROVEAN, PredictSNP) or the combination of these tools, we found accumulation of predicted deleterious variants in patients (p-value range 0.002–0.013; OR range 3.1–5.2). No association was found in the Japanese cohort, in which 13 non-synonymous variants were detected. Functional studies revealed >50% reduced secretion of 7 variants, however, these variants were not significantly enriched in European CP patients.ConclusionOur data indicate that CUZD1 might be a novel susceptibility gene for NACP. How these variants predispose to pancreatitis remains to be elucidated.     

Soft self-expandable metal stent to treat painful pancreatic duct strictures secondary to chronic pancreatitis: a prospective multicenter trial

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Genetic analysis of pancreatic phospholipase A2 (PLA2G1B) in patients with chronic pancreatitis

BackgroundGenetic mutations in various pancreatic enzymes or their counteracting proteins have been linked to chronic pancreatitis. In particular, variants in the genes encoding pancreatic lipase (PNLIP) and carboxyl ester lipase (CEL) have been associated with pancreatitis. Therefore, we investigated pancreatic phospholipase A2 (PLA2G1B) as a promising candidate gene in patients with chronic pancreatitis.MethodsWe analyzed all coding exons and adjacent intronic regions of PLA2G1B in 416 German patients with non-alcoholic chronic pancreatitis (NACP) and 186 control subjects by direct DNA sequencing.ResultsWe detected 2 frequent synonymous variants in exon 3: c.222T>C (p.Y74 = ) and c.294G>A (p.S98 = ). The genotype and allele frequencies of these variants were similar between patients and controls (c.222 TC: 9.6% in NACP vs. 9.7% in controls; c.222CC: 0.2% in NACP vs. 0% in controls; c.294 GA: 31.3% in NACP vs. 28.0% in controls; c.294AA: 2.4% in NACP vs. 1.1% in controls). All p-values were non-significant. In addition, we found one synonymous variant, c.138C>T (p.N46 = ) and one non-synonymous variant, c.244A>G (p.S82G), in a single case each.ConclusionsOur results suggest that genetic alterations in PLA2G1B do not predispose to the development of non-alcoholic chronic pancreatitis.     

Prevalence and predictive factors of undernutrition and low bone mineral density in children with chronic pancreatitis

BackgroundMalnutrition and bone disease are common in adults with chronic pancreatitis (CP). We studied the nutritional status and bone mineral density (BMD) of children with CP and the factors predicting them.MethodsCP children were prospectively evaluated with a detailed questionnaire, anthropometry, 25-hydroxy vitamin D, fecal elastase and BMD [total body less head (TBLH), spine and hip] by dual energy x-ray absorptiometry. Body mass index (BMI) Z score of ?1 to ?1.9, ?2 to ?2.9 and <-3 was taken as mild, moderate and severe malnutrition respectively. Low BMD and osteoporosis were defined as per International Society for Clinical Densitometry.Results83 children (46 boys, 14[4.3–21]years) with CP were enrolled. Majority had Cambridge IV (51,62.2%) or III (15,18.3%) changes. 34(41%) had undernutrition (mild-37.3%, moderate-2.4%, severe-1.2%). Overweight and obesity were present in 3.6% and 1.2% cases. BMI had a significant correlation with haemoglobin, serum albumin, percentage body fat and BMD. A majority had low fecal elastase (69 [84.1%], <100 μg/g) and vitamin D deficiency (70[84.3%],<20 ng/ml). 9 cases had a history of fractures. 14/75(18.6%) cases had low TBLH-BMD and this group had a lower BMI (?1.3[-1.9 to 0.34] vs 0.8 [-2.1 to 5.50; p = 0.03) than patients with normal BMD. There was no difference in age, disease duration, vitamin D, fecal elastase and Cambridge grade between normal and low BMD.Conclusions41% CP children have undernutrition with a majority having mild undernutrition. Nearly 20% have low BMD, with osteoporosis in none. Subjects with low BMI have lower BMD and percentage body fat.     

Loss-of-function variant in chymotrypsin like elastase 3B (CELA3B) is associated with non-alcoholic chronic pancreatitis

BackgroundGenetic alterations in digestive enzymes have been associated with chronic pancreatitis (CP). Recently, chymotrypsin like elastase 3B (CELA3B) emerged as a novel risk gene. Thus, we evaluated CELA3B in two European cohorts with CP.MethodsWe analyzed all 8 CELA3B exons in 550 German non-alcoholic CP (NACP) patients and in 241 German controls by targeted DNA sequencing. In addition, we analyzed exons 6 and 7 by Sanger sequencing and the c.129+1G>A variant by melting curve analysis in 1078 further German controls. As replication cohort, we investigated up to 243 non-German European NACP patients and up to 1665 controls originating from Poland, Hungary, and Sweden. We assessed the cellular secretion and the elastase activity of recombinant CELA3B variants.ResultsIn the German discovery cohort, we detected a splice-site variant in intron 2, c.129+1G>A, in 9/550 (1.64%) CP patients and in 5/1319 (0.38%) controls (P=0.007, OR=4.4, 95% CI=1.5–13.0). In the European replication cohort, this variant was also enriched in patients (9/178 [5.06%]) versus controls (13/1247 [1.04%]) (P=0.001, OR=5.1, 95% CI=2.1–12.0). We did not find the two previously reported codon 90 variants, p.R90C and p.R90L.ConclusionsOur data indicate that CELA3B is a susceptibility gene for CP. In contrast to previous reports suggesting that increased CELA3B activity is associated with CP risk, the splice-site variant identified here is predicted to cause diminished CELA3B expression. How reduced CELA3B function predisposes to pancreatitis remains to be elucidated.     

Impact of etiology on disease course in chronic pancreatitis

BackgroundComplications in chronic pancreatitis (CP) can be grouped in inflammatory (ICC) and fibrotic (FCC) clusters and pancreatic insufficiency cluster (PIC). However, the association between etiological risk factors and the development of complication clusters remains obscure. In this study, the impact of the etiology and disease duration on disease onset and development of complications was investigated.MethodsThis cross-sectional study recruited patients with CP from Mannheim/Germany (n = 870), Gieβen/Germany (n = 100) und Donetsk/Ukraine (n = 104). Etiological risk factors, disease stage, age at disease onset, complications, need for hospitalization and surgery were noted.ResultsIn 1074 patients diagnosed with CP, main risk factors were alcohol and nicotine abuse. An earlier onset of the disease was observed upon nicotine abuse (−4.0 years). Alcohol abuse was only associated with an earlier onset of the definite stage of CP.Alcohol abuse was the major risk factor for the development of ICC (p < 0.0001, multiple regression modeling). Abstinence of alcohol reduced ICC, whereas abstinence of nicotine showed no association. PIC correlated with efferent duct abnormalities and the disease duration. In contrast, FCC was mainly dependent on the disease duration (p < 0.0001; t-test). The presence of any complication cluster correlated with the need for surgery (p < 0.01; X²-test). However, only ICC correlated with a prolonged hospital stay (p < 0.05; t-test).ConclusionsICC is mainly dependent on alcohol abuse. In contrast, FCC and PIC are mainly dependent on the disease duration. The etiology and disease duration can be used as predictors of the course of disease to provide individual treatment and surveillance strategies.     

Pancreatic exocrine insufficiency is a risk factor for kidney stones in patients with chronic pancreatitis

IntroductionMost patients with chronic pancreatitis (CP) develop pancreatic exocrine insufficiency (PEI) over the course of the disease. PEI may lead to hyperoxaluria and development of urinary oxalate stones. It has been postulated that the patients with CP may be at increased risk of kidney stone formation, but the data is scarce. We aimed to estimate incidence and risk factors for nephrolithiasis in a Swedish cohort of patients with CP.Patients and methodsWe performed retrospective analysis of an electronical medical database of patients diagnosed with definite CP during 2003–2020. We excluded patients <18 years of age, those with missing relevant data in medical charts, patients with probable CP (according to the M-ANNHEIM classification system) and those in whom kidney stones were diagnosed before CP diagnosis.ResultsSome 632 patients with definite CP were followed over a median of 5.3 (IQR 2.4–6.9) years. There were 41 (6.5%) patients diagnosed with kidney stones, of whom 33 (80.5%) were symptomatic. Comparing to patients without kidney stones, patients with nephrolithiasis were older, with median age of 65 (IQR 51–72) years, and a male predominance (80% vs 63%). Cumulative incidence of kidney stones was 2.1%, 5.7%, 12.4% and 16.1% at 5, 10, 15, and 20 years after CP diagnosis, respectively. Multivariable cause-specific Cox regression analysis revealed PEI as independent risk factor for nephrolithiasis (adjusted HR 4.95, 95%CI 1.65–14.84; p = 0.004). Another risk factors were increase in BMI (aHR 1.16 95% CI 1.04–1.30; p = 0.001 per unit increment), and a male sex (4.51, 95% CI 1.01–20.3, p = 0.049).ConclusionPEI and increase in BMI are risk factors for kidney stone development in patients with CP. Male CP patents are particularly at increased risk of nephrolithiasis. This should be taken into consideration in general clinical approach to raise awareness among patients and medical workers.     

Fatty acid ethyl ester (FAEE) associated acute pancreatitis: An ex-vivo study using human pancreatic acini

Background & aimFatty acid ethyl esters (FAEEs), are produced by non-oxidative alcohol metabolism and can cause acinar cell damage and subsequent acute pancreatitis in rodent models. Even though experimental studies have elucidated the FAEE mediated early intra-acinar events, these mechanisms have not been well studied in humans. In the present study, we evaluate the early intra-acinar events and inflammatory response in human pancreatic acinar tissues and cells in an ex-vivo model.MethodsExperiments were conducted using normal human pancreatic tissues exposed to FAEE. Subcellular fractionation was performed on tissue homogenates and trypsin and cathepsin B activities were estimated in these fractions. Acinar cell injury was evaluated by histology and immunohistochemistry. Cytokine release from exposed acinar cells was evaluated by performing Immuno-fluorescence. Serum was collected from patients with AP within the first 72 h of symptom onset for cytokine estimation using FACS.ResultsWe observed significant trypsin activation and acinar cell injury in FAEE treated tissue. Cathepsin B was redistributed from lysosomal to zymogen compartment at 30 min of FAEE exposure. IHC results indicated the presence of apoptosis in pancreatic tissue at 1 & 2hrs of FAEE exposure. We also observed a time dependent increase in secretion of cytokines IL-6, IL-8, TNF-α from FAEE treated acinar tissue. There was also a significant elevation in plasma cytokines in patents with alcohol associated AP within 72 h of symptom onset.ConclusionOur data suggest that alcohol metabolites can cause acute acinar cell damage and subsequent cytokine release which could eventually culminant in SIRS.     

Reduction of inflammation in chronic pancreatitis using a soy bread intervention: A feasibility study

IntroductionChronic pancreatitis is a chronic inflammatory disease, which progresses to fibrosis. Currently there are no interventions to delay or stop the progression to irreversible organ damage. In this study, we assessed the tolerability and feasibility of administering soy bread to reduce circulating inflammatory mediators.MethodsSubjects with chronic pancreatitis diagnosed using the American Pancreatic Association diagnostic guidelines were enrolled. During the dose escalation (DE) phase, subjects received one week of soy bread based using a 3 + 3 dose-escalation design, which was then followed by a maximally tolerated dose (MTD) phase with four weeks of intervention. Dose-limiting toxicities (DLTs) were monitored. Plasma cytokine levels were measured using a Meso Scale Discovery multiplex assay kit. Isoflavonoid excretion in 24-h urine collection was used to measure soy bread compliance.ResultsNine subjects completed the DE phase, and one subject completed the MTD phase without any DLTs at a maximum dosage of three slices (99 mg of isoflavones) per day. Reported compliance to soy bread intervention was 98%, and this was confirmed with urinary isoflavones and their metabolites detected in all subjects. There was a significant decline in the TNF-α level during the DE phase (2.667 vs 2.382 pg/mL, p = 0.039); other levels were similar.ConclusionsIn this feasibility study, there was excellent compliance with a short-term intervention using soy bread in chronic pancreatitis. Reduction was seen in at least one pro-inflammatory cytokine with short-term intervention. Larger cohorts and longer interventions with soy are warranted to assess the efficacy of reducing pro-inflammatory mediators of disease.     

Elevated arterial lactate level as an independent risk factor for pancreatic infection in moderately severe acute pancreatitis

PurposeThe present study aimed to research the relationships between arterial lactate levels and pancreatic infection in moderately severe acute pancreatitis.MethodsThis study retrospectively analyzed data from 503 patients with moderately severe acute pancreatitis from January 1, 2013, to March 31, 2018. The baseline characteristics on admission were compared between patients with and without elevated arterial lactate levels. The parameters and laboratory data were compared between patients with and without pancreatic infections at admission. Univariate and multivariate logistic regression analyses were used to assess the value of elevated arterial lactate levels for identifying high-risk patients. P ≤ 0.05 was considered statistically significant.ResultsA total of 49 (9.2%) patients were diagnosed with pancreatic infections. Compared with patients without pancreatic infections, pancreatic infection patients had significantly increased arterial lactate levels at admission (1.5 ± 0.7 vs. 2.5 ± 0.9; P < 0.01). Multivariate logic analysis still showed that higher arterial lactate levels in moderately severe acute pancreatitis was an independent risk factor for developing pancreatic infections (hazard ratio: 6.31, 95% CI 3.01–13.24; P < 0.01). Arterial lactate level ≥2.1 mmol/L and procalcitonin level ≥0.5 ng/mL at admission had area under the receiver operating characteristic curves of 0.83 and 0.72, with sensitivity of 67.2% and 87%, and specificity of 82.0% and 60%, respectively, for the prediction of pancreatic infection in moderately severe acute pancreatitis.ConclusionsOur results indicate that a higher arterial lactate level is independently associated with pancreatic infection in patients with moderately severe acute pancreatitis and may be used as a tool to identify high-risk patients.     

Bone health assessment in clinical practice is infrequenty performed in patients with chronic pancreatitis

BackgroundChronic pancreatitis (CP) patients have a high prevalence of osteoporotic fractures. In addition to prevalence of osteoporotic fractures, we evaluated how often bone health is assessed by dual-energy x-ray absorptiometry (DXA) in clinical practice, and the performance of Fracture Risk Assessment Tool (FRAX®) in predicting fracture risk in CP patients.MethodsMedical records of CP patients age ≥40 years prospectively enrolled in the North American Pancreatitis Study 2 (NAPS2) from the University of Pittsburgh Medical Center from 2000 to 2014 were retrospectively reviewed to gather additional relevant data before, at, and after enrollment until December 2016. We determined if patients underwent DXA, compared their observed prevalence of fractures with published data from two large US studies based on administrative data, and their predicted fracture risk with US population based on FRAX®.ResultsOnly 21% (49/239) patients were evaluated by DXA during their care. The observed cumulative prevalence of fragility fractures in NAPS2 CP patients (9.2%, 95% confidence interval 5.9–13.6) was significantly greater than in controls (1.46% and 2.16%, p ≤ 0.001 for each comparison) and CP patients (4.66%, and 5.13%, p < 0.005 for each comparison) in the two US administrative data studies. The FRAX® 10-year probability of major osteoporotic fracture of ≥20% (5.1% vs. 8.3%, p > 0.05) and for hip fracture of ≥3% (19.6% vs. 18.9%, p > 0.05) in NAPS2 CP patients did not differ from the US population.ConclusionsDespite their high risk of fragility fractures, bone health is infrequently assessed in CP patients. FRAX® may not adequately predict fracture risk in CP patients.     

Acute pancreatitis in intraductal papillary mucinous neoplasms correlates with pancreatic volume and epithelial subtypes

BackgroundIntraductal papillary mucinous neoplasm (IPMN) of the pancreas is associated with acute pancreatitis (AP) in some cases, however its causes have not been fully elucidated. We investigated the association of the incidence of AP with epithelial subtypes and pancreatic volume in IPMN.MethodsThis retrospective study included 182 consecutive surgically resected IPMN patients between January 2000 and December 2018. The relationship between the incidence of AP and epithelial subtypes of IPMN and pancreatic volume was investigated. Epithelial subtypes of IPMN were classified into gastric (G type: N = 116), intestinal (I type: N = 49), pancreatobiliary (PB type: N = 14), and oncocytic types (O type: N = 3). Pancreatic volume of the contrast-enhanced computed tomography scan was measured using Ziostation2 software. Histological pancreatic parenchymal atrophy was also evaluated.ResultsAP occurred more frequently in I-types (I-type vs. G-type, 22.4% [11/49] vs 3.4% [4/116], P = 0.003) and PB-types (PB type vs. G-type, 35.7% [5/14] vs. 3.4% [4/116], P = 0.007) in comparison with G-types, which constituted the majority of the resected IPMNs. AP occurred more frequently in I-type patients with high pancreatic volumes (I-type with high pancreatic volume vs. I-type with low pancreatic volume, 37.0% [10/27] vs. 4.7% [1/21], P = 0.02). However, histological atrophy did not show an additional influence on the association between the incidence of AP and epithelial subtypes. The elevation of serum pancreatic enzymes was not significantly related to epithelial subtypes.ConclusionEpithelial subtypes and the degree of pancreatic volume may be closely associated with the incidence of AP in IPMN.     

American Society for Gastrointestinal Endoscopy guideline on post-ERCP pancreatitis prevention strategies: summary and recommendations

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Exocrine pancreas insufficiency in chronic pancreatitis – Risk factors and associations with complications. A multicentre study of 1869 patients

Background/objectivesThere is scarce information about risk factors for exocrine pancreas insufficiency (EPI) in chronic pancreatitis (CP), and how it associates with other complications. The aim of the present study was to examine risk factors for EPI and associations to procedures and other CP related complications in a large, Northern European cohort.Patients and methodsWe retrieved cross-sectional data on demographics, status on EPI, aetiological risk factors for CP, CP related complications as well as surgical and endoscopic treatment from the Scandinavian Baltic Pancreatic Club Database. Associations were assessed by univariate and multivariate logistic regression analyses. Results are presented as odds ratios (OR) with 95% confidence intervals.ResultsWe included 1869 patients with probable or definitive CP in the study. Exocrine pancreas insufficiency was present in 849 (45.4%) of patients. In multivariate analyses, EPI associated with smoking aetiology (OR 1.47 (1.20–1.79), p < 0.001), and nutritional/metabolic aetiology (OR 0.52 (0.31–0.87), p = 0.01) to CP. Pancreatic or common bile duct stenting procedure and pancreatic resection were both associated with EPI (ORs 1.44 (1.15–1.80), p = 0.002 and 1.54 (1.02–2.33), p = 0.04, respectively). The presence of diabetes mellitus (OR 2.45 (1.92–3.15), p < 0.001), bile duct stenosis (OR 1.48 (1.09–2.00), p = 0.02) and underweight (2.05 (OR 1.40–3.02), p < 0.001) were all associated with presence of EPI.ConclusionsSmoking, bile duct stenosis, previous stenting and resection procedures are all associated with EPI in patients with CP. Presence of EPI were also associated with malnutrition and diabetes mellitus. Hence, intensive nutritional surveillance is needed in these patients.