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Clinical trials demonstrate the short-term efficacy of dual CFTR modulators, but long-term real-world data is limited. We aimed to investigate the effects of 24-month lumacaftor/ivacaftor (LUM/IVA) therapy in pediatric CF patients (pwCF). This observational study included pwCF homozygous for F508del mutation treated between 2021 and 2023. We report data for the first 24 months from therapy initiation. Variables were analyzed separately for ages 2–5, 6–11, and over 12. Data from 49 pwCF (median age: 9.3 years (5.5–14.2)) showed that ppFEV1 values after a transient increase at 12 months, decreased from 102% (82–114) at baseline to 87% (74–96) at 24 months. The decrease was more pronounced with higher initial ppFEV1. Median sweat chloride concentration decreased from 75 mmol/L (69–82) to 57 mmol/L (43–70) without any association with respiratory function change. Median BMI  z -score increased from − 0.81 (− 1.37–0.49) to − 0.39 (− 0.88 to  − 0.04) ( p  = 0.288), and the proportion of underweight and overweight children decreased. Skeletal muscle mass remained stable, while fat mass significantly increased ( p  = 0.011). Fecal elastase levels improved, especially among younger patients. These findings underscore the potential benefits of early initiation of CFTR modulator therapy in pediatric CF patients, highlighting improvements in nutritional status and pancreatic function.

Introduction Pancreatic exocrine insufficiency (PEI) results from a reduction in pancreatic secretion of enzymes, leading to malabsorption of nutrients, intestinal symptoms, nutritional deficiencies and related comorbidities. The diagnosis of pancreatic exocrine insufficiency should be based on digestive tests, mainly the coefficient of fat absorption (CFA), based on the quantification of 72 h fecal fat excretion (FFE). However, this test is rarely performed in clinical practice. Fecal elastase‐1 (FE‐1) is a simple and widely used alternative. This meta‐analysis evaluates the diagnostic accuracy of fecal elastase‐1 for the diagnosis of PEI diagnosed by CFA or 72h‐FFE. Methods A systematic search of databases was performed to identify studies evaluating fecal elastase‐1 and CFA/FFE for the diagnosis of pancreatic exocrine insufficiency. Inclusion criteria required original studies with data on sensitivity, specificity and other diagnostic metrics. Two independent reviewers performed data extraction and quality assessment using the QUADAS‐2 tool. Pooled sensitivity, specificity, likelihood ratios and diagnostic odds ratio (DOR) were calculated and heterogeneity was assessed using I‐squared tests. Results Thirteen studies with 888 patients were included. Fecal elastase‐1 at a cut‐off of 200 μg/g showed a pooled sensitivity and specificity of 0.94 and 0.69, respectively, with a DOR of 35.27. Lowering the cut‐off to 100 μg/g improved specificity to 0.82 but decreased sensitivity to 0.88. Subgroup analyses showed different diagnostic performance in different clinical contexts, with higher sensitivity in cystic fibrosis (0.98) and higher specificity in chronic pancreatitis (0.81). The positive and negative predictive values are limited in situations with low and high probability of pancreatic exocrine insufficiency, respectively. Conclusions Fecal elastase‐1 is a sensitive and moderately specific diagnostic tool for pancreatic exocrine insufficiency and is suitable for initial screening in high‐risk populations. However, its moderate specificity requires careful interpretation in lower risk settings. FE‐1 is a sensitive and moderately specific diagnostic tool for PEI, suitable for initial screening in high risk populations. However, in low‐risk settings, results should be interpreted with caution due to the potential for false positives.

In the last 10 years, several studies have shown that the pancreas of patients with type 1 diabetes (T1D), and even of subjects at risk for T1D, was smaller than the pancreas from healthy subjects. This arose the question of the relationships between the endocrine and exocrine parts of the pancreas in T1D pathogenesis. Our review underlines that histological anomalies of the exocrine pancreas are common in patients with T1D: intralobular and interacinar fibrosis, acinar atrophy, fatty infiltration, leucocytic infiltration, and pancreatic arteriosclerosis are all frequent observations. Moreover, 25% to 75% of adult patients with T1D present with pancreatic exocrine dysfunction. Our review summarizes the putative causal factors for these structural and functional anomalies, including: 1/ alterations of insulin, glucagon, somatostatin and pancreatic polypeptide secretion, 2/ global pancreatic inflammation 3/ autoimmunity targeting the exocrine pancreas, 4/ vascular and neural abnormalities, and 5/ the putative involvement of pancreatic stellate cells. These observations have also given rise to new theories on T1D: the primary event of T1D pathogenesis could be non-specific, e.g bacterial or viral or chemical, resulting in global pancreatic inflammation, which in turn could cause beta-cell predominant destruction by the immune system. Finally, this review emphasizes that it is advisable to evaluate pancreatic exocrine function in patients with T1D presenting with gastro-intestinal complaints, as a clinical trial has shown that pancreatic enzymes replacement therapy can reduce the frequency of hypoglycemia and thus might improve quality of life in subjects with T1D and exocrine failure.

The prevalence of celiac disease (CD) is approximately 1% in the US. Studies have shown possible association between exocrine pancreatic insufficiency (EPI) and CD, with numerous hypothesized biological mechanisms including small bowel mucosal damage causing disruption of enteric-mediated hormonal secretion such as cholecystokinin and loss of enterokinase. The overall prevalence of EPI in CD remains unknown. We performed systematic review and metanalysis and examined the prevalence of EPI in patients who were first diagnosed with CD versus those who had been on treatment with gluten-free diet (GFD). Results Six studies were included in the analysis totaling 446 CD patients (Avg age 44.1 years; 34% Males). One hundred and forty-four patients had newly diagnosed CD, and 302 patients had known CD with at least 9 months treatment with GFD. Four studies examined newly diagnosed CD patients. The individual rates of EPI in new CD patients ranged from 10.5 to 46.5%. The pooled prevalence of EPI in newly diagnosed CD patients was 26.2% (95% CI 8.43–43.92%, Q = 2.24, I2 = 0%). Five studies examined CD patients on GFD. The rate of EPI ranged from 1.9% to 18.2%. The prevalence of EPI in patients treated with GFD is 8% (95% CI 1.52–14.8%, Q = 4.42, I2 = 9.59%). Patients with newly diagnosed CD are significantly more likely to have EPI compared to those patients treated with GFD (p = 0.031). CD patients on GFD with persistent symptoms have a significantly higher rate of EPI (28.4%) compared to CD patients on GFD who are asymptomatic (3%) (p < 0.001).

Pancreatic exocrine insufficiency (PEI) is defined as a reduction in pancreatic exocrine secretion below the level that allows the normal digestion of nutrients. Pancreatic disease and surgery are the main causes of PEI. However, other conditions and upper gastrointestinal surgery can also affect the digestive function of the pancreas. PEI can cause symptoms of nutritional malabsorption and deficiencies, which affect the quality of life and increase morbidity and mortality. These guidelines were developed following the United European Gastroenterology framework for the development of high‐quality clinical guidelines. After a systematic literature review, the evidence was evaluated according to the Oxford Center for Evidence‐Based Medicine and the Grading of Recommendations Assessment, Development, and Evaluation methodology, as appropriate. Statements and comments were developed by the working groups and voted on using the Delphi method. The diagnosis of PEI should be based on a global assessment of symptoms, nutritional status, and a pancreatic secretion test. Pancreatic enzyme replacement therapy (PERT), together with dietary advice and support, are the cornerstones of PEI therapy. PERT is indicated in patients with PEI that is secondary to pancreatic disease, pancreatic surgery, or other metabolic or gastroenterological conditions. Specific recommendations concerning the management of PEI under various clinical conditions are provided based on evidence and expert opinions. This evidence‐based guideline summarizes the prevalence, clinical impact, and general diagnostic and therapeutic approaches for PEI, as well as the specifics of PEI in different clinical conditions. Finally, the unmet needs for future research are discussed.

Purpose of ReviewType 1 and type 2 diabetes are often accompanied by mostly mild forms of exocrine pancreatic insufficiency. Despite high prevalence, little is known about the clinical consequences of exocrine pancreatic insufficiency and its optimal (nutritional) treatment. Even less is known if and to what extent exocrine pancreas insufficiency also affects glycemic control in diabetes. This article aims for summarizing current clinical knowledge on screening, diagnosis, and treatment and gives an overview on the pathophysiology of exocrine pancreatic insufficiency in diabetes.Recent FindingsRecent studies reveal novel insights into the close interaction of acinar, ductal, and endocrine cells and the gut-pancreas axis.SummaryExocrine pancreatic insufficiency is a clinically relevant, frequent but poorly understood disorder in both type 1 and type 2 diabetes.

Backgrounds We aimed to monitor pancreatic exocrine function longitudinally in relation to the development of islet autoimmunity (IA) and type 1 diabetes (T1D) in at‐risk children with a first‐degree relative with T1D, who were followed prospectively in the Environmental Determinants of Islet Autoimmunity (ENDIA) study. Methods Fecal elastase‐1 (FE‐1) concentration was measured longitudinally in 85 ENDIA children from median age 1.0 (IQR 0.7,1.3) year. Twenty‐eight of 85 children (progressors) developed persistent islet autoantibodies at median age of 1.5 (IQR 1.1,2.5) years, of whom 11 went on to develop clinical diabetes. The other 57 islet autoantibody‐negative children (non‐progressors) followed similarly were age and gender‐matched with the progressors. An adjusted linear mixed model compared FE‐1 concentrations in progressors and non‐progressors. Results Baseline FE‐1 did not differ between progressors and non‐progressors, or by HLA DR type or proband status. FE‐1 decreased over time in progressors in comparison to non‐progressors (Wald statistic 5.46, P = .02); in some progressors the fall in FE‐1 preceded the onset of IA. Conclusions Pancreatic exocrine function decreases in the majority of young at‐risk children who progress to IA and T1D.

Background Exocrine pancreatic insufficiency (EPI) can be associated with all types of diabetes. Pancreatic enzyme replacement therapy (PERT) has short and long-term benefits in subjects with EPI, but its effects on diabetes control are uncertain. We aimed to study the effects of PERT initiation on glycemic control in subjects with diabetes and EPI from any cause. Methods In this retrospective study, we compared subjects with EPI and diabetes who were prescribed PERT with subjects with diabetes who had a fecal elastase-1 concentration dosage, but did not receive PERT. The primary outcome was the effect of PERT on hypoglycemia frequency and severity. The secondary outcomes were the effects of PERT on gastro-intestinal disorders, HbA 1c and body mass index (BMI). Results 48 subjects were included in each group. Overall, PERT did not have any significant effect on hypoglycemia frequency or severity, but hypoglycemia frequency tended to decrease in subjects with chronic pancreatitis. While 19% of subjects experienced mild hyperglycemia after PERT initiation, we did not report any keto-acidosis or any other severe adverse event. Gastro-intestinal disorders improved in 80% of subjects treated with PERT, versus in 20% of control subjects ( p  = 0.02). Gastro-intestinal disorders improved in 87% of subjects with recommended dosage of PERT, versus in 50% of subjects with underdosage (NS). HbA 1c and BMI evolution did not differ between the groups. Conclusions PERT initiation is safe in subjects with diabetes and EPI. It does not globally decrease hypoglycemia severity of frequency, but is associated with a decrease in gastro-intestinal disorders. Trial registration Retrospectively registered. The database was registered with the Commission Nationale Informatique et Libertés (CNIL), registration number: 2203351v0. The study was approved by the local ethics committee CLEP, registration number: AAA-2023-09047

Exocrine pancreatic insufficiency (EPI) is suspected but remains understudied in immunosuppressed conditions such as post‐hematopoietic stem cell transplantation (HSCT). This prospective observational study aimed to investigate the incidence, impact, and risk factors of EPI in a cohort of 83 pediatric and young adult patients who underwent allogeneic HSCT at Charité ‐ Universitätsmedizin Berlin between 2020 and 2023. Fecal pancreatic elastase (PE) measurements and transabdominal ultrasound were utilized to evaluate pancreatic function over a one‐year period. Secondary analysis explored the association of EPI with clinical complications and included a multivariable regression analysis of potential risk factors. Low PE levels significantly correlated with pathological pancreatic imaging findings, independent of concurrent diarrhea. EPI was suspected in 45% (32/71) of patients (95%CI: [34.1%, 56.6%]), with 29% (13/45) (95%CI: [17.7%, 43.4%]) showing signs of prolonged EPI (pEPI) lasting at least 8 weeks. After excluding cases with confounding factors such as missing enteral nutrition and diarrhea, the cumulative incidence of prolonged EPI was 20% (8/41) (95%CI: 10.2%–34.0%) in the overall cohort. EPI was associated with weight loss, prolonged dependence on parenteral nutrition, and extended hospitalizations. Adenovirus (ADV) infection emerged as a significant risk factor for EPI (hazard ratio 3.22 [95%CI:1.26–8.2], p = 0.014), along with additional factors such as higher BMI pre‐HSCT, pre‐existing pancreatic damage and early post‐HSCT fasting. The persistence of pancreatic atrophy and EPI beyond two years post‐HSCT in individual cases suggests a potential for permanent pancreatic damage. This study underscores that EPI is a common complication following HSCT, with ADV infection being an important risk factor. The findings support routine PE measurements and early initiation of pancreatic enzyme replacement therapy (PERT), alongside aggressive treatment of ADV infections. Further research is necessary to evaluate the effects of PERT in this population and to explore the applicability of these findings in other immunosuppressed groups.

Background Fatty pancreas disease (FPD) is characterized by abnormal fat accumulation in pancreatic tissue and is often associated with obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). While its pathophysiology and impact on pancreatic functions have been explored, the interplay between FPD, glycemic control, and exocrine dysfunction in T2DM remains inadequately defined. This study aimed to evaluate the presence of FPD, the factors affecting it, and its relationship with endocrine and exocrine pancreatic functions in newly diagnosed T2DM. Methods A total of 126 individuals were included in the study, comprising 63 newly diagnosed T2DM patients and 63 healthy controls matched for age, sex, body mass index and body fat distribution. Body composition, biochemical parameters (glucose, insulin, C-peptide, HbA1c), fecal elastase levels, and pancreatic/hepatic steatosis grades (evaluated using ultrasonography) were assessed. Results Newly diagnosed T2DM patients presented significantly higher hepatic steatosis grades (p = 0.018) and lower fecal elastase levels (p < 0.001) compared to controls. Pancreatic exocrine insufficiency was more prevalent in the T2DM group (p < 0,001). A positive correlation was observed between the FPD grade, hepatic steatosis grade, and hepatic fat fraction. A negative and statistically significant correlation (p < 0.05) was observed between FPD grade and fecal elastase level (r = -0.264). HbA1c levels demonstrated a nonlinear (inverse U-shaped) relationship with FPD, peaking at 9.8% and declining thereafter, while showing a continuous negative relationship with fecal elastase levels. HbA1c predicted low fecal elastase (< 200 μg/g) with a cutoff value of 7.4%. Patients with HbA1c levels > 9.8% presented with reduced FPD alongside persistent exocrine insufficiency. Conclusions Fatty pancreas disease is closely associated with hepatic steatosis, glycemic control, and exocrine pancreatic dysfunction in newly diagnosed T2DM patients. The interplay between FPD, glycemic control, and exocrine dysfunction highlights the need for comprehensive metabolic assessments in this population.