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Background Dietary fat malabsorption contributes to poor nutritional status in patients with cystic fibrosis (CF) and exocrine pancreatic insufficiency (EPI). Prescribing gastric acid-reducing agents such as proton-pump inhibitors (PPI) as an adjunct to pancreatic enzyme replacement therapy (PERT) to improve dietary fat absorption has been accepted in clinical practice despite limited evidence. Aims This was a pilot randomized, double-blind, placebo-controlled crossover trial of subjects aged 12 and older with CF and EPI assessed on placebo and omeprazole to determine if PPI improved the efficacy of PERT as indicated by measures of dietary fat absorption. Methods Fat malabsorption via stool coefficient of fat absorption (CFA) and malabsorption blood test (MBT), gastrointestinal pH (wireless motility capsule [WMC]), and quality of life (QOL) were assessed after 14 days on both placebo or PPI (omeprazole). Results Total 19 subjects enrolled, 13 were randomized, and 9 provided paired results on placebo and PPI. The 3 subject results for CFA were as follows: 1 increased, 1 decreased, and 1 was within the reference range in both tests for fat absorption. For 9 MBT subjects, 7 decreased and 2 increased fat absorption. For the 4 WMC studies, no change in transit times, nor in pH profiles were noted. No differences were seen in the domains of the two QOL questionnaires comparing placebo and PPI. Conclusions These limited descriptive pilot study results in participants with CF and EPI on PERT evaluated by stool, blood, and QOL tests did not suggest improvement in fat absorption attributable to PPI.

In the primary analysis of a 12-month double-blind randomized active placebo-controlled trial, treatment of children with cystic fibrosis (CF) and pancreatic insufficiency (PI) with a readily absorbable structured lipid (Encala™, Envara Health, Wayne, PA) was safe, well-tolerated and improved dietary fat absorption (stool coefficient of fat absorption [CFA]), growth, and plasma fatty acids (FA). To determine if the Encala™ treatment effect varied by severity of baseline fat malabsorption. Subjects (n = 66, 10.5±3.0 yrs, 39% female) with baseline CFA who completed a three-month treatment with Encala™ or a calorie and macronutrient-matched placebo were included in this subgroup analysis. Subjects were categorized by median baseline CFA: low CFA (<88%) and high CFA (≥88%). At baseline and 3-month evaluations, CFA (72-hour stool, weighed food record) and height (HAZ), weight (WAZ) and BMI (BMIZ) Z-scores were calculated. Fasting plasma fatty acid (FA) concentrations were also measured. Subjects in the low CFA subgroup had significantly improved CFA (+7.5±7.2%, mean 86.3±6.7, p = 0.002), and reduced stool fat loss (-5.7±7.2 g/24 hours) following three months of EncalaTM treatment. These subjects also had increased plasma linoleic acid (+20%), α-linolenic acid (+56%), and total FA (+20%) (p≤0.005 for all) concentrations and improvements in HAZ (0.06±0.08), WAZ (0.17±0.16), and BMIZ (0.20±0.25) (p≤0.002 for all). CFA and FA were unchanged with placebo in the low CFA group, with some WAZ increases (0.14±0.24, p = 0.02). High CFA subjects (both placebo and Encala™ groups) had improvements in WAZ and some FA. Subjects with CF, PI and more severe fat malabsorption experienced greater improvements in CFA, FA and growth after three months of Encala™ treatment. Encala™ was safe, well-tolerated and efficacious in patients with CF and PI with residual fat malabsorption and improved dietary energy absorption, weight gain and FA status in this at-risk group.

Predicting severe acute pancreatitis (AP) remains a challenge. The present study compares admission blood urea nitrogen (BUN), hematocrit, and creatinine, as well as changes in their levels over 24 h, aiming to determine the most accurate laboratory test for predicting persistent organ failure and pancreatic necrosis. Clinical data of 1,612 AP patients, enrolled prospectively in three independent cohorts (University of Pittsburgh, Brigham and Women's Hospital, Dutch Pancreatitis Study Group), were abstracted. The predictive accuracy of the studied laboratories was measured using area under the receiver-operating characteristic curve (AUC) analysis. A pooled analysis was conducted to determine their impact on the risk for persistent organ failure and pancreatic necrosis. Finally, a classification tree was developed on the basis of the most accurate laboratory parameters. Admission hematocrit ≥44% and rise in BUN at 24 h were the most accurate in predicting persistent organ failure (AUC: 0.67 and 0.71, respectively) and pancreatic necrosis (0.66 and 0.67, respectively), outperforming the other laboratory parameters and the acute physiology and chronic health evaluation-II score. In a pooled analysis, admission hematocrit ≥44% and rise in BUN at 24 h were associated with an odds ratio of 3.54 and 5.84 for persistent organ failure, and 3.11 and 4.07, respectively, for pancreatic necrosis. In addition, the classification tree illustrated that when both admission hematocrit was ≥44% and BUN levels increased at 24 h, the rates of persistent organ failure and pancreatic necrosis reached 53.6% and 60.3%, respectively. Admission hematocrit ≥44% and rise in BUN at 24 h may be the optimal predictive tools in clinical practice among existing laboratory parameters and scoring systems.

Background Malnutrition and weight loss are commonly observed in patients with pancreatic cancer and contribute to poor survival. Pancreatic exocrine insufficiency (PEI), which can be caused by ductal obstruction by a tumor, causes maldigestion and malabsorption of nutrients, thus contributing to malnutrition in these patients. In this study, we evaluated the effects of pancreatic enzyme replacement therapy (PERT) on survival in patients with unresectable pancreatic cancer. Methods A retrospective analysis was conducted on a database of patients with unresectable, pathologically confirmed pancreatic cancer. All patients were evaluated for palliative chemotherapy and received the optimal palliative care. Patients were divided into two groups: Group 1 received standard therapy; Group 2 underwent additional evaluation of the pancreatic function and therapy with PERT, if needed. Survival (median and 95% confidence interval [CI]) was analyzed using Kaplan–Meier and Cox regression; groups were compared using the log-rank test. Results Overall, 160 patients with unresectable pancreatic cancer were included in the analysis (mean age: 70.5 years [range 28–100]; gender: 57.5% male; tumor stage: 78.7% Stage IV). Eighty-six patients (53.75%) were in Group 1 and 74 (46.25%) were in Group 2. Age, gender, tumor size, location and stage, weight loss, and serum CA 19–9 were similar between groups. Ninety-three (58.1%) patients received palliative chemotherapy; 46.5% in Group 1 and 71.6% in Group 2 ( P  < 0.001). Forty-nine (66.2%) patients in Group 2 and none in Group 1 received PERT. Survival in Group 2 (189 days, 95% CI 167.0–211.0 days) was significantly longer than in Group 1 (95.0 days, 95% CI 75.4–114.6 days) (HR 2.117, 95% CI 1.493–3.002; P  < 0.001). Chemotherapy and PERT were significantly and independently associated with longer survival in a model controlled by age and tumor stage. In patients with significant weight loss at diagnosis (> 10% bodyweight within 6 months), PERT was associated with longer survival (HR 2.52, 95% CI 1.55–4.11; P  < 0.001). Conclusions In patients with unresectable pancreatic cancer, PERT in patients with PEI was associated with longer survival compared with those not receiving PERT, especially in those experiencing significant weight loss. This finding should guide future prospective clinical trials of similar interventions.

Malignancy is accompanied by changes in the metabolism of both cells and the organism 1 , 2 . Pancreatic ductal adenocarcinoma (PDAC) is associated with wasting of peripheral tissues, a metabolic syndrome that lowers quality of life and has been proposed to decrease survival of patients with cancer 3 , 4 . Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic 5 , 6 . Here we show that loss of both adipose and muscle tissue occurs early in the development of pancreatic cancer. Using mouse models of PDAC, we show that tumour growth in the pancreas but not in other sites leads to adipose tissue wasting, suggesting that tumour growth within the pancreatic environment contributes to this wasting phenotype. We find that decreased exocrine pancreatic function is a driver of adipose tissue loss and that replacement of pancreatic enzymes attenuates PDAC-associated wasting of peripheral tissues. Paradoxically, reversal of adipose tissue loss impairs survival in mice with PDAC. When analysing patients with PDAC, we find that depletion of adipose and skeletal muscle tissues at the time of diagnosis is common, but is not associated with worse survival. Taken together, these results provide an explanation for wasting of adipose tissue in early PDAC and suggest that early loss of peripheral tissue associated with pancreatic cancer may not impair survival. Pancreatic ductal adenocarcinoma in mice induces loss of adipose tissue through altered function of the exocrine pancreas, and supplementing pancreatic enzymes attenuates the wasting of peripheral tissues induced by pancreatic cancer.

The aim of this study was to elucidate the impact of porcine pancreatic enzymes (Creon® pancrelipase) in comparison to microbial-derived alpha amylase (MD amylase) on the small intestine wall structure, mucosal glycogen accumulation, and enterocyte turnover. The impact of enzyme supplementation on the small intestine was explored in 18 pigs with surgically induced exocrine pancreatic insufficiency (EPI). Four healthy pigs served as the control group. EPI led to reduced villus length, crypt depth, and thickness of the mucosa and muscularis layers compared to those of healthy pigs. All these changes appeared to be reversible after enzyme supplementation. Brush border thickness was decreased in EPI and increased with both enzyme preparations, with MD amylase treatment leading to the highest values in the proximal jejunum. No EPI-induced changes were observed in the goblet cell (GC) population, but significant increases in GC number and area were observed following MD amylase treatment. Glycogen accumulation within the duodenal mucosa was significantly increased in EPI pigs. EPI was also shown to significantly increase apoptotic activity and decrease proliferative activity in comparison to healthy animals, while both enzyme preparations resulted in the complete recovery of both proliferative and apoptotic activity in all investigated intestinal segments. Creon® influenced the morphology of the small intestine. However, supplementation of exogenous microbial amylase alone also affected gut morphology in a similar way to that of the complex host pancreatic enzymes offered orally. These data indicate that in addition to their role in digestion of nutrients in EPI, intraluminal pancreatic enzymes, especially amylase, contribute to gut health through maintenance of the intestinal wall architecture and physiological enterocyte turnover.

Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency, and bony abnormalities with an increased risk of myeloid neoplasia. Almost all cases of SDS result from biallelic mutations in Shwachman-Bodian-Diamond syndrome (SBDS). SBDS interacts with elongation factor–like 1 (EFL1) to displace eukaryotic initiation factor 6 (EIF6) from the 60S ribosomal subunit. Released EIF6 permits the assembly of ribosomal large and small subunits in the cytoplasm. Decreased EIF6 levels due to haploinsufficiency or missense mutations, which lead to decreased protein expression, may provide a somatic genetic rescue and antileukemic effects. We observed accumulation of EIF6 protein in sbds -KO zebrafish models, confirmed this accumulation in patient-derived tissues, and correlated these with changes in ribosomal proteins and tumor protein p53 (TP53) pathways. The mechanism of action for this adaptive response is unknown. To address this, we generated eif6 -KO zebrafish, which do not survive more than 10 days after fertilization. We also created 2 mutants with low Eif6 expression, i.e., 5%–25% of WT levels, that could survive until adulthood. We bred them with sbds -null strains and analyzed their phenotype and biochemical properties. Low Eif6 levels reduced Tp53 pathway activation but did not rescue neutropenia in Sbds-deficient zebrafish. Further studies elucidating the interplay between SBDS, EIF6, and TP53 and cellular stress responses offer promising insights into SDS pathogenesis, somatic genetic rescue, and therapeutic strategies.

Chronic pancreatitis (CP) can lead to pancreatic exocrine insufficiency (PEI), causing protein malabsorption and altered amino acid levels. Our aim is to investigate amino acid levels in patients with CP and to assess the associations with exocrine insufficiency, pancreatic elastography, and the severity of CP. Twenty-five patients with CP were prospectively enrolled in this study. A control group included 28 age- and gender-matched subjects without pancreatic disease. Amino acids were quantified using the Biocrates MxP Quant 500 kit. Differences in amino acid levels were calculated using the non-parametric Wilcoxon test. Pancreatic stiffness was evaluated by EUS-elastography, PEI was assessed using fecal elastase-1 levels. The severity of CP was determined using the M-ANNHEIM classification. The ratio of nonessential amino acids to essential amino acids, glutamic acid and aspartic acid levels were significantly increased in the CP group, whereas tryptophan levels were significantly decreased in CP. A positive correlation between proteinogenic amino acids and the severity of pancreatitis was found. Proline levels showed a strong correlation with the CP severity index (r = 0.63), a significant correlation with elastase-1 values (r = -0.48, p = 0.02), and a moderate correlation with pancreatic stiffness (r = 0.47, p = 0.09). Patients with CP have altered amino acid blood levels, an increased ratio of nonessential to essential amino acids. The severity of CP was found to increase the levels of nonessential amino acids, with proline showing the strongest associations with severity, elastase-1 levels, and pancreatic stiffness.

Obesity is associated with increased risk for developing pancreatic cancer, and it is suggested that insulin resistance provides the missing link. Here we demonstrate that under the context of genetic susceptibility, a high fat diet (HFD) predisposes mice with oncogenic K-ras activation to accelerated pancreatic intraepithelial neoplasm (PanIN) development. Tumor promotion is closely associated with increased inflammation and abrogation of TNFR1 signaling significantly blocks this process underlining a central role for TNFα in obesity-mediated enhancement of PanIN lesions. Interestingly, however, despite increased TNFα levels, mice remain insulin sensitive. We show that, while aggravating tumor promotion, a HFD exerts dramatic changes in energy metabolism through enhancement of pancreatic exocrine insufficiency, metabolic rates, and expression of genes involved in mitochondrial fatty acid (FA) β-oxidation that collectively contribute to improved glucose tolerance in these mice. While on one hand these findings provide significant evidence that obesity is linked to tumor promotion in the pancreas, on the other it suggests alterations in inflammatory responses and bioenergetic pathways as the potential underlying cause.

The Johanson-Blizzard syndrome (JBS) is a complex autosomal recessive disorder that manifests through a spectrum of symptoms, with deficiencies in the ubiquitin-protein ligase E3 component N-recognin 1 (UBR-1) at its genetic core. Despite its clinical significance, the molecular intricacies of UBR-1's role in JBS remain largely elusive, presenting a formidable challenge in devising targeted treatments. The nematode , with its genetic tractability and conservation of fundamental biological mechanisms, emerges as an invaluable model for unravelling the molecular underpinnings of JBS. This review integrates the latest discoveries from studies, shedding light on UBR-1's multiple functions: its regulatory impact on cellular pathways and, particularly, its crucial involvement in glutamate metabolism. By assessing the contributions of these studies to our understanding of JBS, this review highlights the potential significance of glutamate metabolic dysfunction in JBS pathogenesis.