Search Results (130)

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive tumor biology and profound host vulnerability, including pancreatic exocrine insufficiency (PEI), maldigestion, malnutrition, cachexia, sarcopenia, frailty, systemic inflammation, and poor tolerance to multimodal therapy. Gut and intratumoral microbiota have been implicated in pancreatic carcinogenesis, tumor immunity, chemotherapy response, and postoperative outcomes. However, the clinical readiness of microbiome-informed supportive care in PDAC remains uncertain. Results: Current evidence supports plausible mechanistic links among PEI, maldigestion, dysbiosis, microbial metabolites, barrier dysfunction, systemic inflammation, cachexia, sarcopenia, and treatment intolerance. Nevertheless, PDAC microbiome research is limited by major heterogeneity in sampling sites, sequencing platforms, antibiotic exposure, biliary drainage, diet, treatment timing, tumor stage, and analytic pipelines. Evidence is also discordant, particularly regarding alpha diversity and reproducible microbial signatures. Low-biomass tissue contamination and incomplete consideration of fungal and multi-kingdom microbiota further limit interpretation. Conclusions: Microbiome disturbance should currently be viewed as an investigational modifier of nutritional vulnerability and treatment tolerance rather than as a validated clinical biomarker or therapeutic target in PDAC. A clinically responsible framework should distinguish what is actionable now—nutrition screening, PEI management, inflammation and frailty assessment, body-composition evaluation, and treatment-exposure monitoring—from what remains investigational, including microbiome profiling, microbial signatures, probiotics, prebiotics, fecal microbiota transplantation, and metabolite-guided intervention. Full article

Vitamin A plays an important role in multiple homeostatic functions such as vision, immunity, epithelial cell integrity and differentiation, cell signaling, pulmonary function, reproduction, growth, and development. Vitamin A deficiency was described in people with cystic fibrosis (pwCF) due to a multitude of causes, such as suboptimally managed exocrine pancreatic insufficiency, advanced cystic fibrosis-related liver disease (aCFLD), and a history of intestinal resection, and is generally rare in contemporary practice. Apart from true vitamin A deficiency, low vitamin A levels may also be noted in various inflammatory states, as vitamin A is a negative acute-phase reactant. In the current era of cystic fibrosis (CF) transmembrane-conductance regulator (CFTR)-directed therapies, there is a paradigm shift in vitamin A status, with deficiency statuses becoming rarer, and instead higher serum vitamin levels (in some cases, even in the hypervitaminosis range) are increasingly reported. People with aCFLD, renal insufficiency, post-lung transplantation, and pregnancy are prone to vitamin A toxicity. Hence, CF clinicians should be proactive in evaluating these abnormalities and proficient in managing both deficiency and toxicity, as both these conditions can be associated with adverse outcomes. In this review, we detailed the basics of vitamin A metabolism, manifestations of both vitamin A deficiency and excess, and their clinical implications in pwCF. Full article

Background: Vitamin D deficiency is common in patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Whether vitamin D status influences tumor aggressiveness and clinical outcomes remains uncertain. This review examines current evidence on the prevalence, determinants, clinical associations, and clinical relevance of vitamin D deficiency in GEP-NENs. Methods: A narrative and critical review of the literature was conducted using the PubMed/MEDLINE, Scopus, and Web of Science databases. Clinical studies, observational cohorts, translational research, selected mechanistic studies, and current clinical guidelines addressing vitamin D metabolism and neuroendocrine neoplasms were evaluated. Results: Vitamin D deficiency has been reported in approximately 60–80% of patients with GEP-NENs. Low serum 25-hydroxyvitamin D concentrations likely reflect multiple disease-related factors, including malabsorption, pancreatic exocrine insufficiency, chronic diarrhea, previous gastrointestinal surgery, and nutritional impairment. Several observational studies have linked lower vitamin D status with markers of more aggressive disease, including higher Ki-67 proliferation index values and shorter progression-free survival. Nevertheless, the available data are heterogeneous, predominantly observational, and do not support a causal relationship between vitamin D deficiency and tumor progression. At present, the main clinical rationale for assessing vitamin D status is to support metabolic care, preserve bone health, and prevent osteoporosis. Conclusions: Vitamin D deficiency is a frequent and clinically relevant comorbidity in patients with GEP-NENs. Although lower vitamin D status has been associated with markers of more aggressive disease, current findings do not support vitamin D supplementation as an anticancer treatment strategy. Prospective clinical and translational studies are needed to clarify the biological and clinical significance of vitamin D signaling in GEP-NENs. Full article

Background/Objectives: Exocrine pancreatic insufficiency (EPI) is increasingly recognized in patients with diabetes; however, its clinical correlates remain poorly defined. This study aimed to determine the prevalence and clinical characteristics of EPI in patients with type 1 (T1DM) and type 2 diabetes mellitus (T2DM) and to evaluate its associations with diabetes-related complications and insulin therapy. Methods: A total of 200 patients with diabetes were screened, and 182 who met the inclusion criteria were included in the final analysis. EPI was diagnosed using fecal elastase-1 (FE-1). Clinical, biochemical, and complication-related data were collected. Factors associated with EPI were evaluated using univariate and multivariate logistic regression analyses. Among patients with T2DM, an inverse probability of treatment weighting–average treatment effect on the treated (IPTW-ATT) model was constructed to evaluate the association between insulin therapy and EPI. Propensity scores were estimated using baseline demographic and clinical covariates, and covariate balance after weighting was assessed using standardized mean differences (SMDs). Results: Exocrine pancreatic insufficiency was detected in 18.1% of patients, with prevalences of 21.2% in T1DM and 17.4% in T2DM. Cardiovascular disease was the only variable independently associated with EPI in multivariate analysis (OR = 3.25; 95% CI: 1.12–6.75; p = 0.028. Among patients with T2DM, insulin therapy was significantly associated with EPI in both unadjusted and IPTW-ATT analyses (weighted OR = 10.76; 95% CI: 1.85–62.76; p = 0.008) with a wide confidence interval reflecting sparse data. Cardiovascular disease also remained significantly associated with EPI in the weighted model (OR = 3.52; 95% CI: 1.22–10.15; p = 0.020). Conclusions: Exocrine pancreatic insufficiency is a clinically relevant condition in diabetes and shows a significant cross-sectional association with cardiovascular disease. In T2DM, insulin therapy was associated with a higher prevalence of EPI, although confounding by indication cannot be excluded. These findings suggest that evaluation of exocrine pancreatic function may be considered in high-risk diabetic subgroups, pending confirmation in prospective longitudinal studies. Full article

Background: Currently, increasing attention is being paid to the role of genes other than CFTR and their variants as factors modifying the course of cystic fibrosis (CF). One such gene is SLC26A9, which encodes a protein involved in chloride and bicarbonate transport across the epithelial cell membrane. Variants of SLC26A9, such as c.229G>A (p.Gly77Ser) and c.1885C>T (p.Pro629Ser), have been described in patients with severe and rapidly progressive CF. The aim of this study was to identify SLC26A9 variants in a group of 20 patients with CF. Methods: DNA was isolated from blood samples and collected from all patients. Fragments of exons 3 and 17 of the SLC26A9 gene were amplified by PCR and sequenced using the Sanger method. Results: An SLC26A9 variant was identified in two siblings. These patients were diagnosed with CF in adulthood and presented with moderate pulmonary symptoms without exocrine pancreatic insufficiency. In both siblings carrying the CFTR variants p.Phe508del and c.3140-26A>G, the SLC26A9 variant c.1847C>T (p.Pro616Leu) was detected. This variant has not been widely described in the literature and has not previously been associated with CF. Conclusions: The c.1847C>T (p.Pro616Leu) variant is located near a domain that may affect the transport function of the SLC26A9 protein. However, patients in whom the variant was identified did not present a severe disease phenotype. Further studies on larger patient cohorts are required, and at present this variant should be considered of uncertain significance in CF. Full article

Autoimmune pancreatitis (AIP) represents a rare multifaceted disorder group with currently three types that were recently supplemented by a newly described AIP type causally related to sunlight exposure, not previously reported in any of the AIP publications. The internet search disclosed that the new AIP type was different from three existing AIP types: the AIP-1 or AIP-2 types, both featured by idiopathy, and the AIP-3 type, triggered by immune checkpoint inhibitors. Accordingly, it seemed appropriate to classify the novel AIP as the AIP-4 type, with typical features such as a clear culprit of sunlight exposure, ascertained by a positive result of an unintentional re-exposure and considered a diagnostic gold standard; coexisting secondary sclerosing cholangitis without progression to vanishing bile duct syndrome; and ultimately unavoidable pancreatic atrophy with clinical exocrine insufficiency despite long-term treatment with immunosuppressive drugs. Thus, the recent description of a new AIP type, now classified as the AIP-4 type, is strongly associated with significant sunlight exposure and calls for a reclassification of AIP types that includes AIP-4, whereby additional efforts are essential to identify the causative factors of the AIP-1 and AIP-2 types, including drugs commonly used in the respective cohorts, which also comprise older patients with comorbidities. Full article

Background: Acute pancreatitis (AP) is increasingly recognised as a disease with clinically significant long-term consequences. However, the extent to which aetiology influences the spectrum of long-term pancreatic sequelae remains unclear. This systematic review and meta-analysis evaluated long-term complications following a first episode of AP, with a protocol-defined focus on the impact of aetiology. Methods: This review evaluated eligible studies that included adults with a first episode of AP who were followed for chronic pancreatitis (CP), exocrine pancreatic insufficiency (EPI), or new-onset diabetes mellitus (NODM). A comprehensive search of PubMed, Scopus, Web of Science, and CENTRAL was conducted from January 2002 to June 2025. Risk of bias was assessed using the Newcastle–Ottawa Scale. Random-effects meta-analyses were performed to estimate pooled incidence proportions. A prespecified network meta-analysis was not feasible because outcome-specific event counts stratified by aetiology were inconsistently reported. This study satisfied PRISMA 2020 guidelines and was registered with PROSPERO (CRD420251074032). Results: Eight studies met eligibility criteria with extractable data for quantitative synthesis. Five studies (n ≈ 10,780) reported chronic pancreatitis (CP), with a pooled incidence of approximately 7–8% following a first episode of acute pancreatitis (AP) and substantial heterogeneity (I² ≈ 96%). Three studies (n = 796) reported exocrine pancreatic insufficiency (EPI), with a pooled incidence of approximately 23%, although estimates were highly heterogeneous (I² ≈ 98%). Four studies (n = 2706; 415 events) reported new-onset diabetes mellitus (NODM), with a pooled incidence of approximately 20% (I² ≈ 93%). Although aetiology-specific quantitative comparisons were not possible, narrative synthesis consistently demonstrated higher long-term risk following alcohol-associated AP, lower risk after biliary AP, and intermediate but variable outcomes in idiopathic AP. Conclusions: Clinically meaningful long-term pancreatic dysfunction is common after a first episode of acute pancreatitis, particularly new-onset diabetes mellitus. While aetiology-specific risks could not be quantified, consistent patterns suggest that aetiology shapes long-term outcomes. These findings support structured, aetiology-informed follow-up after acute pancreatitis and the need for standardised outcome reporting in future studies. Full article

Background and Objectives: Functional dyspepsia (FD) often overlaps with Pancreatic Exocrine Insufficiency (PEI), leading to diagnostic delays. We aimed to evaluate the prevalence of PEI in patients presenting dyspeptic symptoms using the survey-based PEI test and to assess the clinical response to Pancreatic Enzyme Replacement Therapy (PERT). Methods: This study included 91 patients with PEI and 58 control subjects. PEI was evaluated using the PEI Patient-Reported Outcome (PRO) instrument and classified as mild, moderate, or severe according to the 18-item PEI test. Objective fat malabsorption was assessed by the acid steatocrit method using a gravimetric assay. Patients diagnosed with PEI received PERT, and treatment response was evaluated at follow-up with a repeat PEI test. Results: When the case and control groups were compared in terms of PEI scores, a statistically significant difference was found (p < 0.001). Fecal steatocrit value was found to be statistically significant with the PEI score (p = 0.017). No statistically significant difference was found between amylase, lipase, vitamin D, vitamin B12, and folic acid and the PEI score (p = 0.789, p = 0.299, p = 0.865, p = 0.153, and p = 0.855, respectively). A statistically significant difference was found between the pre-treatment PEI score and the post-treatment PEI score (p < 0.001). The mean pre-treatment PEI score was 1.52 ± 0.50, while the post-treatment PEI score was 0.42 ± 0.48. Approximately 72% reduction in PEI score was observed with treatment. Conclusions: The PEI test may represent a useful, non-invasive tool for identifying suspected pancreatic dysfunction in patients initially diagnosed with functional dyspepsia. Early integration of this tool into clinical practice can improve symptom control and prevent the misclassification of PEI as a purely functional disorder. Full article

The introduction of cystic fibrosis transmembrane conductance regulator modulators (CFTRms) in the treatment of cystic fibrosis (CF) has significantly improved both the life expectancy and quality of life for patients affected by the disease. While this new therapy shows promising results in CF patients, data about the use of CFTRms during pregnancy in women who are carriers with fetuses affected by CF are limited. We present a new case report and literature review of fetal CF treated by the maternal assumption of CFTRms to understand the safety and the effectiveness of the treatment in resolving fetal and neonatal CF clinical manifestations (meconium ileus, postnatal exocrine pancreatic insufficiency, and postnatal intestinal surgery). Our report represents the fifth unsuccessful case of fetal CF treated in utero by CFTRms and highlights the potential key elements necessary for a successful treatment. Full article

Veterinary metabolomics has redefined bile acids (BAs) from simple digestive surfactants to systemic endocrine signals within a microbial–host metabolic axis. This review aims to evaluate how BA dysmetabolism acts as a central pathogenic factor in canine and feline disease. We analyze the BA pool’s integrity, which depends on a specialized functional guild, primarily Peptacetobacter hiranonis, responsible for 7α-dehydroxylation. We delineate two principal pathological profiles: (1) microbial collapse, characterized by secondary bile acid (SBA) depletion and compromised farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) signaling, which exacerbates inflammation in chronic enteropathy (CE), protein-losing enteropathy (PLE), and exocrine pancreatic insufficiency (EPI); and (2) hepato-biliary spillover, wherein host-induced dysfunction results in primary bile acid (PBA) excess. Recent data have linked these disruptions to skeletal health, feline renal fibrosis, cardiac remodeling in myxomatous mitral valve disease (MMVD), and neuroinflammation in epilepsy and hepatic encephalopathy. The discovery of microbially conjugated bile acids (MCBAs) and microbial extracellular vesicles (MEVs) reveals highly specific, vesicle-mediated communication pathways impacting systemic health. Diagnostic protocols should prioritize functional profiling, including the dysbiosis index (DI), serum conjugated BA analysis, and SBA/PBA ratios. Clinical management is moving beyond empirical fecal microbiota transplantation (FMT), towards precision synthetic microbial consortia (SynComs), neuroprotective BAs like tauroursodeoxycholic acid (TUDCA), and molecular postbiotics to restore the collaborative metabolome. Full article

Cystic fibrosis (CF) is caused by loss-of-function variants in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride and bicarbonate channel and affects multiple organs, with pancreatic involvement showing very high penetrance. In pancreatic ducts, CFTR drives secretion of alkaline, bicarbonate-rich fluid that maintains intraductal patency, neutralises gastric acid and permits safe delivery of digestive enzymes. Selective impairment of CFTR-dependent bicarbonate transport, even in the presence of residual chloride conductance, is strongly associated with exocrine pancreatic insufficiency, recurrent pancreatitis and cystic-fibrosis-related diabetes. These clinical manifestations are captured by pharmacodynamic anchors such as faecal elastase-1, steatorrhoea, pancreatitis burden and glycaemic control, providing clinically meaningful benchmarks for CFTR-targeted therapies. In this review, we summarise the principal mechanisms underlying pancreatic pathophysiology and the current approaches to clinical management. We then examine in vitro pancreatic duct models that are used to evaluate small molecules and emerging therapeutics targeting CFTR. These experimental systems include native tissue, primary cultures, organoids, co-cultures and microfluidic devices, each of which has its own advantages and limitations. Intact micro-perfused ducts provide the physiological benchmark for studying luminal pH control and bicarbonate (HCO₃⁻) secretion. Primary pancreatic duct epithelial cells (PDECs) and pancreatic ductal organoids (PDO) preserve ductal identity, patient-specific genotype and key regulatory networks. Immortalised ductal cell lines grown on permeable supports enable scalable screening and structure activity analyses. Co-culture models and organ-on-chip devices incorporate inflammatory, stromal and endocrine components together with flow and shear and provide system-level readouts, including duct-islet communication. Across this complementary toolkit, we prioritise bicarbonate-relevant endpoints, including luminal and intracellular pH and direct measures of HCO₃⁻ flux, to improve alignment between in vitro pharmacology and clinical pancreatic outcomes. The systematic use of complementary models should facilitate the discovery of next-generation CFTR modulators and adjunctive strategies with the greatest potential to protect both exocrine and endocrine pancreatic function in people with CF. Full article

We aimed to highlight the roles of the pancreatic enzymes, with special reference to amylase, on glucose homeostasis in healthy pigs and in pigs with exocrine pancreatic insufficiency (EPI). Healthy pigs fed a high-fat diet (HFD) were subjected to mixed meal tolerance tests (MMTTs) and pancreatic enzyme treatments, and then blood glucose and insulin concentrations were determined. Following the development of surgically induced EPI, the same experiment was then repeated on the pigs. A significantly lower net postprandial glycemic response was observed in pigs with EPI compared to healthy pigs. Net postprandial glycemic response was not affected by enzyme supplementation during the MMTTs in healthy pigs, but it was affected by adaptation to macronutrient components of the MMTT test meal, both in healthy and EPI pigs. Net postprandial glycemic response and insulin release curves reached higher levels in Creon-treated EPI pigs compared to amylase-treated EPI pigs. In summary, glucose homeostasis mechanisms in EPI pigs were downregulated compared to healthy animals. Creon supplementation during EPI significantly increased postprandial glucose level, while amylase treatment had the opposite effect, which could be explained by its metabolic actions. Full article

Background: Vitamin D (VD) insufficiency is present in chronic pancreatitis (CP), leading to increased cardiovascular risk, bone complications, impaired quality of life, and increased mortality. This study aimed to determine the prevalence of VD deficiency in patients with CP and to assess its relationship to CP progression and associated cardiovascular complications. Methods: Seventy patients were enrolled and evaluated for pancreatic exocrine insufficiency by fecal elastase-1, CP severity by M-ANNHEIM classification, cardiovascular risk by 10-year risk mortality scores (SCORE and FRS), and for arterial stiffness using pulse wave velocity (PWV) at a. carotis and a. femoralis. Determination of 25-hydroxyvitamin D was performed by an LC-MS/MS method. Resting energy expenditure was calculated using the Harris–Benedict formula. Results: Mean VD levels were 37.86 ± 24.36 nmol/L (range 3.854–99.874 nmol/L); only five patients were in sufficiency status. VD levels correlated significantly with body mass index (BMI) and resting energy expenditure. In patients with severe structural changes, we observed lower VD levels regardless of etiology (p < 0.01). VD levels were lower in patients with pancreatic exocrine insufficiency (PEI), p < 0.05. Patients with mild CP by M-ANNHEIM had lower levels of VD compared to moderate and advanced CP, p < 0.05. At a cut-off of VD 11.95 nmol/L, we verified pancreatic lithiasis with 89.4% sensitivity, 83.3% specificity, and AUC of 0.826 ± 0.113 (95% CI, 0.61–1). VD status worsened with the increase in the 10-year risk mortality by both SCORE and FRS and PWV, p < 0.05. Conclusions: Most of our patients with CP were VD insufficient. Monitoring of nutritional status in patients with CP is mandatory to prevent the development of malnutrition complications and the associated morbidity and mortality. Full article

Background: Surgical procedures and alterations of the gastrointestinal (GI) tract increase the risk of small intestinal bacterial overgrowth (SIBO), which is associated with GI symptoms and complications that compromise postoperative recovery. However, the prevalence and clinical impact of SIBO after various upper GI surgical procedures remain poorly understood. Objective: This study aimed to evaluate the prevalence of SIBO after different types of upper GI surgery and to investigate the associated clinical factors. Methods: We conducted an observational study involving 157 patients with a history of upper GI surgery: Roux-en-Y gastric bypass (RYGB), laparoscopic single-anastomosis gastric bypass (OAGB), subtotal (STG) or total gastrectomy (TG), subtotal (SP)or total pancreatectomy (TP), cephalic duodenopancreatectomy (WR), and small bowel resection for Crohn’s disease. A glucose–hydrogen breath test was performed, and demographic, clinical, and treatment-related data were collected. Statistical analyses included t-tests, non-parametric tests, ANOVA, and correlation analyses using R software. Results: At a median follow-up of 25.7 ± 18.1 months, 31% (48/157) of patients tested positive for SIBO. The highest prevalence was observed after RYGB and OAGB (43%), followed by TG (30%), STG (29%), TP/WR (28%), and Crohn’s disease bowel resection (19%). No cases of SIBO were observed after SP. SIBO positivity was significantly associated with bloating and flatulence (p = 0.002), lactose intolerance (p = 0.047), systemic sclerosis (p = 0.042), T2D (p = 0.002), and exposure to adjuvant chemotherapy (p = 0.001) and radiotherapy (p = 0.027). In addition, the risk of SIBO increased proportionally with the duration of GI resection or exclusion (p = 0.013). Conclusions: In our study, the prevalence of SIBO after upper GI surgery was 31%, with the highest incidence (43%) observed in metabolic surgery patients. Importantly, adjuvant radio/chemotherapy was associated with an increased risk of SIBO, and extensive small bowel resection or exclusion was strongly associated with an increased risk of SIBO. Furthermore, the limitations of current diagnostic methods, which lack sufficient sensitivity and specificity, highlight the importance of early screening and standardization of diagnostic techniques to improve patient management and outcomes. Full article

Introduction: After total pancreatectomy, patients inevitably develop pancreatogenic diabetes with marked glycemic variability and high risk of malnutrition due to both endocrine and exocrine insufficiency. Weight loss and malnutrition can occur even in those with adequate dietary intake and plausible pancreatic enzyme replacement. We hypothesized that glycemic variability is associated with nutritional decline. Methods: We retrospectively analyzed 14 patients who underwent continuous glucose monitoring (CGM) after total pancreatectomy. Nutritional status was assessed using the Geriatric Nutritional Risk Index (GNRI), and patients were classified into malnutrition-risk progression or nutrition-maintaining groups. Then, we evaluated glycemic indices, dietary intake, anthropometry, and pancreatic enzyme replacement therapy (PERT). Results: Insulin use, PERT dose, and dietary intake were approximately comparable between groups. In contrast, the malnutrition-risk progression group showed significantly higher mean glucose and time above range, and lower time in range (TIR). Importantly, TIR consistently showed an inverse association with malnutrition-risk progression across models adjusted for clinical covariates, including time since pancreatectomy, primary diagnosis, insulin regimen, and pancrelipase dose. These findings indicate that the observed relationship between lower TIR and worsening GNRI was independent of dietary intake and adequacy of enzyme replacement therapy, underscoring TIR as a clinically meaningful indicator of nutritional decline in this population. Conclusions: Hyperglycemia and reduced TIR were significantly associated with worsening GNRI after total pancreatectomy, independent of dietary intake or PERT. CGM-based glycemic metrics may help identify patients at risk of malnutrition and guide postoperative management. Full article