Pancreatic Enzyme Use Reduces Pancreatitis Frequency in Children With Acute Recurrent or Chronic Pancreatitis: A Report From INSPPIRE.

INTRODUCTION: Among children who suffer from acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP), acute pancreatitis (AP) episodes are painful, often require hospitalization, and contribute to disease complications and progression. Despite this recognition, there are currently no interventions to prevent AP episodes. In this retrospective cohort study, we assessed the impact of pancreatic enzyme therapy (PERT) use on clinical outcomes among children with pancreatic-sufficient ARP or CP. METHODS: Children with pancreatic-sufficient ARP or CP in the INSPPIRE-2 cohort were included. Clinical outcomes were compared for those receiving vs not receiving PERT, as well as frequency of AP before and after PERT. Logistic regression was used to study the association between development of AP episodes after starting PERT and response predictors. RESULTS: Among 356 pancreatic-sufficient participants, 270 (76%) had ARP, and 60 (17%) received PERT. Among those on PERT, 42% did not have a subsequent AP episode, during a mean 2.1 years of follow-up. Children with a SPINK1 mutation ( P = 0.005) and those with ARP (compared with CP, P = 0.008) were less likely to have an AP episode after starting PERT. After initiation of PERT, the mean AP annual incidence rate decreased from 3.14 down to 0.71 ( P < 0.001). DISCUSSION: In a retrospective analysis, use of PERT was associated with a reduction in the incidence rate of AP among children with pancreatic-sufficient ARP or CP. These results support the need for a clinical trial to evaluate the efficacy of PERT to improve clinical outcomes among children with ARP or CP.

Impact of Elevated Serum Triglycerides on Children with Acute Recurrent or Chronic Pancreatitis from INSPPIRE-2.

OBJECTIVE: To determine if mild-moderate hypertriglyceridemia (HTG) is associated with increased development of chronic pancreatitis (CP) or pancreatitis-associated complications in children with acute recurrent or CP. STUDY DESIGN: Longitudinal data from the INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2) cohort of children with acute recurrent or CP (n = 559) were analyzed. Subjects were divided into normal triglycerides (<150 mg/dL; 1.7 mmol/L), any HTG (≥150 mg/dL; ≥1.7 mmol/L), mild-moderate HTG (150-499 mg/dL; 1.7-5.6 mmol/L), moderate HTG (500-999 mg/dL; 5.6-11.3 mmol/L), and severe HTG groups (≥1000 mg/dL; ≥11.3 mmol/L), based on highest serum triglyceride value. Laboratory, imaging, pancreatitis and hospital events, complications, and quality of life data were analyzed. RESULTS: In children with acute recurrent or CP and HTG, there was no increase in the number of pancreatitis attacks per person-years, nor an increase in CP prevalence. However, HTG severity was associated with increased pancreatic inflammation, pancreatic cysts, pain, hospital days, number of hospitalizations, intensive care, and missed school days. CONCLUSIONS: Mild-moderate HTG in children with acute recurrent or CP was not associated with increased pancreatitis frequency, nor increased development of CP, but was associated with increased pancreatitis complications and disease burden. As a treatable condition, treatment of mild-moderate HTG may be considered to reduce pancreatitis-associated complications and medical burden in children with acute recurrent or CP.

Pediatric-to-Adult Transfer of Care in Patients With Pancreas Disease: Recommendations for Care and Research Opportunities.

Young adults who have experienced recurrent acute pancreatitis and chronic pancreatitis as children or adolescents are vulnerable to poor follow-up and disease management during the transfer from the pediatric to adult healthcare system. Although formalized transition programs for young adults have been developed and described for other disease conditions, no such program has been described for young adults with pancreatic disease. This document is the first expert opinion outlining the important aspects of a transitional care and transfer program tailored to youth with recurrent acute and chronic pancreatitis. We emphasize the unique needs of these patients as they transfer to adult health care and the need for further research. The goal of improved transitional care and transfer is to enhance the services provided to adolescents/young adults with pancreatic disease in both healthcare settings and improve continuity of follow-up care.

Bone health in children with recurrent and chronic pancreatitis: A multi-center cross sectional analysis.

BACKGROUND/OBJECTIVES: Bone health of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) is not well studied. METHODS: This retrospective study was performed at three sites and included data from INSPPIRE-2. RESULTS: Of the 87 children in the study: 46 had ARP (53%), 41 had CP (47%). Mean age was 13.6 ± 3.9 years at last DXA scan. The prevalence of low height-for-age (Z-score < -2) (13%, 10/78) and low bone mineral density (BMD) adjusted for height (Z-score < -2) (6.4%, 5/78) were higher than a healthy reference sample (2.5%, p < 0.0001 and p = 0.03, respectively). CONCLUSION: Children with ARP or CP have lower height and BMD than healthy peers. Attention to deficits in growth and bone mineral accrual in children with pancreatic disease is warranted.

Pediatric Drug-Associated Pancreatitis Reveals Concomitant Risk Factors and Poor Reliability of Causality Scoring: Report From INSPPIRE.

OBJECTIVES: Drug-associated acute pancreatitis (DAP) studies typically focus on single acute pancreatitis (AP) cases. We aimed to analyze the (1) characteristics, (2) co-risk factors, and (3) reliability of the Naranjo scoring system for DAP using INSPPIRE-2 (the INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2) cohort study of acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) in children. METHODS: Data were obtained from ARP group with ≥1 episode of DAP and CP group with medication exposure ± DAP. Physicians could report multiple risk factors. Pancreatitis associated with Medication (Med) (ARP+CP) was compared to Non-Medication cases, and ARP-Med vs CP-Med groups. Naranjo score was calculated for each DAP episode. RESULTS: Of 726 children, 392 had ARP and 334 had CP; 51 children (39 ARP and 12 CP) had ≥1 AP associated with a medication; 61% had ≥1 AP without concurrent medication exposure. The Med group had other risk factors present (where tested): 10 of 35 (28.6%) genetic, 1 of 48 (2.1%) autoimmune pancreatitis, 13 of 51 (25.5%) immune-mediated conditions, 11 of 50 (22.0%) obstructive/anatomic, and 28 of 51 (54.9%) systemic risk factors. In Med group, 24 of 51 (47%) had involvement of >1 medication, simultaneously or over different AP episodes. There were 20 ARP and 4 CP cases in "probable" category and 19 ARP and 7 CP in "possible" category by Naranjo scores. CONCLUSIONS: Medications were involved in 51 of 726 (7%) of ARP or CP patients in INSPPIRE-2 cohort; other pancreatitis risk factors were present in most, suggesting a potential additive role of different risks. The Naranjo scoring system failed to identify any cases as "definitive," raising questions about its reliability for DAP.

The fatty acid imbalance of cystic fibrosis exists at birth independent of feeding in pig and ferret models.

Persons with cystic fibrosis (CF) exhibit a unique alteration of fatty acid composition, marked especially among polyunsaturates by relative deficiency of linoleic acid and excess of Mead acid. Relative deficiency of docosahexaenoic acid is variably found. However, the initial development of these abnormalities is not understood. We examined fatty acid composition in young CF ferrets and pigs, finding abnormalities from the day of birth onward including relative deficiency of linoleic acid in both species. Fatty acid composition abnormalities were present in both liver and serum phospholipids of newborn CF piglets even prior to feeding, including reduced linoleic acid and increased Mead acid. Serum fatty acid composition evolved over the first weeks of life in both non-CF and CF ferrets, though differences between CF and non-CF persisted. Although red blood cell phospholipid fatty acid composition was normal in newborn animals, it became perturbed in juvenile CF ferrets including relative deficiencies of linoleic and docosahexaenoic acids and excess of Mead acid. In summary, fatty acid composition abnormalities in CF pigs and ferrets exist from a young age including at birth independent of feeding and overlap extensively with the abnormalities found in humans with CF. That the abnormalities exist prior to feeding implies that dietary measures alone will not address the mechanisms of imbalance.

An assessment of pancreatology education in North American pediatric gastroenterology fellowship programs.

BACKGROUND/OBJECTIVES: Within the last two decades, an increased incidence of acute pancreatitis (AP) has been reported in childhood, with some progressing to acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). Training future pancreatologists is critical to improve the care of children with pancreatic diseases. There are no studies to assess whether the pediatric gastroenterology (GI) fellowship curriculum prepares specialists to care for children with pancreatic diseases. METHODS: An electronic survey was distributed to all North American Pediatric Gastroenterology Fellows. The survey included 31 questions on pancreatology training including academic resources, research experience, clinical exposure, clinical confidence, and career plans. RESULTS: A total of 112 (25.8%) fellows responded from 41 (41/72, 56.9%) training centers in North America. Pancreas-specific didactic lectures were reported by 90.2% (n = 101); 49.5% (50/101) had at least quarterly or monthly lectures. Clinical confidence (Likert 4-5) was highest in managing and treating AP (94.6% and 93.8% respectively), relatively lower for ARP (84.8% and 71.4%) and lowest for CP (63.4% and 42.0%). Confidence in diagnosing both ARP and CP was associated with the variety of pancreatic diseases seen (p < 0.001) and total number of patients followed over a 6 month period (p = 0.04). Nine (8%) reported interest in specializing in pancreatology, 12 (10.7%) in pursuing research in the pancreatology. CONCLUSIONS: Trainee confidence is highest in managing AP, lowest in CP, and seems to be directly correlated with the variety of pancreatic diseases and number of patients followed. Continued commitment is necessary to foster training of the next generation of pediatric pancreatologists.

Interobserver Agreement for CT and MRI Findings of Chronic Pancreatitis in Children: A Multicenter Ancillary Study Under the INSPPIRE Consortium.

BACKGROUND. Imaging findings represent key criteria for diagnosing chronic pancreatitis in children. Understanding radiologists' agreement for imaging findings is critical to standardizing and optimizing diagnostic criteria. OBJECTIVE. The purpose of this study is to evaluate the interobserver agreement among experienced pediatric radiologists for subjective, quantitative, and semiquantitative imaging findings of chronic pancreatitis in children. METHODS. In this retrospective study, CT or MRI examinations performed in children with chronic pancreatitis were submitted by six sites participating in the INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a Cure) Consortium. One pediatric radiologist from each of the six sites reviewed examinations; three of the radiologists independently reviewed all CT examinations, and the other three radiologists independently reviewed all MRI examinations. Reviewers recorded 13 categoric imaging findings of chronic pancreatitis and measured pancreas thickness and pancreatic duct diameter. Agreement was assessed using kappa coefficients for the categoric variables and intraclass correlation coefficients (ICCs) for the continuous variables. RESULTS. A total of 76 CT and 80 MRI examinations performed in 110 children (65 girls and 45 boys; mean age, 11.3 ± 4.6 [SD] years) were reviewed. For CT, kappa coefficients for categoric findings ranged from -0.01 to 0.81, with relatively high kappa coefficients noted for parenchymal calcifications (κ = 0.81), main pancreatic duct dilatation (κ = 0.63), and atrophy (κ = 0.52). ICCs for parenchymal thickness measurements ranged from 0.57 in the pancreas head to 0.80 in the body and tail. The ICC for duct diameter was 0.85. For MRI, kappa coefficients for categoric findings ranged from -0.01 to 0.74, with relatively high kappa coefficients noted for main duct irregularity (κ = 0.74), side branch dilatation (κ = 0.70), number of dilated side branches (κ = 0.65), and main duct dilatation (κ = 0.64); kappa coefficient for atrophy was 0.52. ICCs for parenchymal thickness measurements ranged from 0.53 for the neck and body individually to 0.68 in the tail. ICC for duct diameter was 0.77. CONCLUSION. Interobserver agreement was fair to moderate for most CT and MRI findings of chronic pancreatitis in children. CLINICAL IMPACT. This study highlights challenges for the imaging diagnosis of pediatric chronic pancreatitis. Standardized and/or objective criteria are needed given the importance of imaging in diagnosis.

The Role of Surgical Management in Chronic Pancreatitis in Children: A Position Paper From the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Pancreas Committee.

OBJECTIVES: Chronic pancreatitis (CP) is rare in childhood but impactful because of its high disease burden. There is limited literature regarding the management of CP in children, specifically about the various surgical approaches. Herein, we summarize the current pediatric and adult literature and provide recommendations for the surgical management of CP in children. METHODS: The literature review was performed to include the scope of the problem, indications for operation, conventional surgical options as well as total pancreatectomy with islet autotransplantation, and outcomes following operations for CP. RESULTS: Surgery is indicated for children with debilitating CP who have failed maximal medical and endoscopic interventions. Surgical management must be tailored to the patient's unique needs, considering the anatomy and morphology of their disease. A conventional surgical approach (eg, drainage operation, partial resection, combination drainage-resection) may be considered in the presence of significant and uniform pancreatic duct dilation or an inflammatory head mass. Total pancreatectomy with islet autotransplantation is the best surgical option in patients with small duct disease. The presence of genetic risk factors often portends a suboptimal outcome following a conventional operation. CONCLUSIONS: The morphology of disease and the presence of genetic risk factors must be considered while determining the optimal surgical approach for children with CP. Surgical outcomes for CP are variable and depend on the type of intervention. A multidisciplinary team approach is needed to assure that the best possible operation is selected for each patient, their recovery is optimized, and their immediate and long-term postoperative needs are well-met.

Analysis of INSPPIRE-2 Cohort: Risk Factors and Disease Burden in Children With Acute Recurrent or Chronic Pancreatitis.

OBJECTIVES: The objective of this study is to investigate risk factors and disease burden in pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). METHODS: Data were obtained from INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2), the largest multi-center prospective cohort study in pediatric patients with ARP or CP. RESULTS: Of 689 children, 365 had ARP (53%), 324 had CP (47%). CP was more commonly associated with female sex, younger age at first acute pancreatitis (AP) attack, Asian race, family history of CP, lower BMI%, genetic and obstructive factors, PRSS1 mutations and pancreas divisum. CFTR mutations, toxic-metabolic factors, medication use, hypertriglyceridemia, Crohn disease were more common in children with ARP. Constant or frequent abdominal pain, emergency room (ER) visits, hospitalizations, medical, endoscopic or surgical therapies were significantly more common in CP, episodic pain in ARP. A total of 33.1% of children with CP had exocrine pancreatic insufficiency (EPI), 8.7% had diabetes mellitus. Compared to boys, girls were more likely to report pain impacting socialization and school, medical therapies, cholecystectomy, but no increased opioid use. There was no difference in race, ethnicity, age at first AP episode, age at CP diagnosis, duration of disease, risk factors, prevalence of EPI or diabetes between boys and girls. Multivariate analysis revealed that family history of CP, constant pain, obstructive risk factors were predictors of CP. CONCLUSIONS: Children with family history of CP, constant pain, or obstructive risk factors should raise suspicion for CP.

Health-Related Quality of Life in Pediatric Acute Recurrent or Chronic Pancreatitis: Association With Biopsychosocial Risk Factors.

OBJECTIVES: Abdominal pain, emergency department visits, and hospitalizations impact lives of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). Data on health-related quality of life (HRQOL) in this population, however, remains limited. We aimed to evaluate HRQOL in children with ARP or CP; and test biopsychosocial risk factors associated with low HRQOL. METHODS: Data were acquired from the INternational Study Group of Pediatric Pancreatitis: In search for a cuRE registry. Baseline demographic and clinical questionnaires, the Child Health Questionnaire (measures HRQOL) and Child Behavior Checklist (measures emotional and behavioral functioning) were completed at enrollment. RESULTS: The sample included 368 children (54.3% girls, mean age = 12.7years, standard deviation [SD] = 3.3); 65.2% had ARP and 34.8% with CP. Low physical HRQOL (M = 38.5, SD = 16.0) was demonstrated while psychosocial HRQOL (M = 49.5, SD = 10.2) was in the normative range. Multivariate regression analysis revealed that clinical levels of emotional and behavioral problems (B = -10.28, P  < 0.001), episodic and constant abdominal pain (B = 04.66, P = 0.03; B = -13.25, P < 0.001) were associated with low physical HRQOL, after accounting for ARP/CP status, age, sex, exocrine, and endocrine disease (F [9, 271] = 8.34, P < 0.001). Borderline and clinical levels of emotional and behavioral problems (B = -10.18, P < 0.001; B = -15.98, P < 0.001), and constant pain (B = -4.46, P < 0.001) were associated with low psychosocial HRQOL (F [9, 271] = 17.18, P < 0.001). CONCLUSIONS: Findings highlight the importance of assessing HRQOL and treating pain and psychosocial problems in this vulnerable group of children.

Acute pancreatitis-induced islet dysfunction in ferrets.

BACKGROUND: /Objectives: The pathogenesis of hyperglycemia during acute pancreatitis (AP) remains unknown due to inaccessibility of human tissues and lack of animal models. We aimed to develop an animal model to study the mechanisms of hyperglycemia and impaired glucose tolerance in AP. METHODS: We injected ferrets with intraperitoneal cerulein (50 µg/kg, 9 hourly injections) or saline. Blood samples were collected for glucose (0, 4, 8, 12, 24h); TNF-α, IL-6 (6h); amylase, lipase, insulin, glucagon, pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP) (24h). Animals underwent oral glucose tolerance test (OGTT), mixed meal tolerance test (MMTT) at 24h or 3 months, followed by harvesting pancreas for histopathology and immunostaining. RESULTS: Cerulein-injected ferrets exhibited mild pancreatic edema, neutrophil infiltration, and elevations in serum amylase, lipase, TNF-α, IL-6, consistent with AP. Plasma glucose was significantly higher in ferrets with AP at all time points. Plasma glucagon, GLP-1 and PP were significantly higher in cerulein-injected animals, while plasma insulin was significantly lower compared to controls. OGTT and MMTT showed abnormal glycemic responses with higher area under the curve. The hypoglycemic response to insulin injection was completely lost, suggestive of insulin resistance. OGTT showed low plasma insulin; MMTT confirmed low insulin and GIP; abnormal OGTT and MMTT responses returned to normal 3 months after cerulein injection. CONCLUSIONS: Acute cerulein injection causes mild acute pancreatitis in ferrets and hyperglycemia related to transient islet cell dysfunction and insulin resistance. The ferret cerulein model may contribute to the understanding of hyperglycemia in acute pancreatitis.

Vascular Complications in Pediatric Pancreatitis: A Case Series.

ABSTRACT: We reviewed INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a Cure) database for splanchnic venous thrombosis or arterial pseudoaneurysms to determine the incidence, risk factors and outcomes of peripancreatic vascular complications in children with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). Of 410 children with diagnostic imaging studies, vascular complications were reported in five (1.2%); two had ARP, three CP. The vascular events were reported during moderately severe or severe acute pancreatitis (AP) in four, mild AP in one. Venous thrombosis occurred in four, arterial pseudoaneurysm (left gastric artery) in one. Two patients with venous thrombosis were treated with anticoagulant, one achieved recanalization (splenic vein). In two patients who did not receive anticoagulants, one re-canalized. No adverse effects were observed with anticoagulants. The child with pseudoaneurysm underwent aneurysmal coiling. Anti-coagulants appear to be safe in children with acute pancreatitis, their long-term benefit needs to be further investigated.

Pancreatitis in Children.

Acute, acute recurrent, and chronic forms of pancreatitis have been increasingly diagnosed in children in the past 2 decades. Risk factors in the pediatric group are broad and appear to be strikingly different compared with the adult cohort. However, the disease burden and impact on quality of life are surprisingly similar in children and adults. This review summarizes the definitions, epidemiology, risk factors, diagnosis, and management of pediatric pancreatitis, identifies features that are unique to the childhood-onset disease, identifies gaps, and proposes recommendations for future opportunities.

Recurrent Pancreatitis in Children: Past, Present, and Future.

Recurrent acute and chronic pancreatitis are increasingly recognized in childhood. Etiologies are vastly different in children compared with adults and mostly involve genetic and anatomical factors with negligible contribution of environmental risks. Pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) have significant impact on quality of life with high healthcare costs. Children with these conditions suffer from recurrent acute or chronic abdominal pain and they endure multiple emergency room visits, hospitalizations, procedures, and surgeries. Diagnostic methods are being developed; treatment options are limited. This review summarizes the most recent developments in pediatric ARP and CP. These discoveries will help physicians provide optimal care for children with these conditions.

Factors Associated With Frequent Opioid Use in Children With Acute Recurrent and Chronic Pancreatitis.

OBJECTIVES: The aim of the study was to understand the association of frequent opioid use with disease phenotype and pain pattern and burden in children and adolescents with acute recurrent (ARP) or chronic pancreatitis (CP). METHODS: Cross-sectional study of children <19 years with ARP or CP, at enrollment into the INSPPIRE cohort. We categorized patients as opioid "frequent use" (daily/weekly) or "nonfrequent use" (monthly or less, or no opioids), based on patient and parent self-report. RESULTS: Of 427 children with ARP or CP, 17% reported frequent opioid use. More children with CP (65%) reported frequent opioid use than with ARP (41%, P = 0.0002). In multivariate analysis, frequent opioid use was associated with older age at diagnosis (odds ratio [OR] 1.67 per 5 years, 95% confidence interval [CI] 1.13-2.47, P = 0.01), exocrine insufficiency (OR 2.44, 95% CI 1.13-5.24, P = 0.02), constant/severe pain (OR 4.14, 95% CI 2.06-8.34, P < 0.0001), and higher average pain impact score across all 6 functional domains (OR 1.62 per 1-point increase, 95% CI 1.28-2.06, P < 0.0001). Children with frequent opioid use also reported more missed school days, hospitalizations, and emergency room visits in the past year than children with no frequent use (P < 0.0002 for each). Participants in the US West and Midwest accounted for 83% of frequent opioid users but only 56% of the total cohort. CONCLUSIONS: In children with CP or ARP, frequent opioid use is associated with constant pain, more healthcare use, and higher levels of pain interference with functioning. Longitudinal and prospective research is needed to identify risk factors for frequent opioid use and to evaluate nonopioid interventions for reducing pain and disability in these children.

Clinical and Practice Variations in Pediatric Acute Recurrent or Chronic Pancreatitis: Report From the INSPPIRE Study.

OBJECTIVE: The aim of the study was to determine whether clinical characteristics and management of pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) differ across INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In Search for a cuRE) sites. STUDY DESIGN: Data were collected from INSPPIRE and analyzed per US regions and "non-US" sites. Between-group differences were compared by Pearson chi-square test. Differences in disease burden were compared by Kruskal-Wallis test. RESULTS: Out of the 479 subjects, 121 (25%) were enrolled in West, 151 (32%) Midwest, 45 Northeast (9%), 78 (16%) South, and 84 (18%) at non-US sites. Hispanic ethnicity was more common in South (P < 0.0001); white race in Northeast (P = 0.009). CP was less common and time from diagnosis of first acute pancreatitis to CP was longer in children at non-US sites (P = 0.0002 and P = 0.011, respectively). Genetic mutations were most common among all groups; PRSS1 variants predominated in Midwest (P = 0.002). Gallstones were more frequent in South (P = 0.002). Endoscopic retrograde cholangiopancreatography (ERCP) and computed tomography (CT) imaging were more commonly utilized in United States compared with non-United States (P < 0.0001), but there were no differences in the use of MRI/MRCP. Disease burden was highest in the West and Midwest, possibly as total pancreatectomy and islet autotransplantation (TPIAT) referral sites were located in these regions. All therapies were less commonly administered in non-US sites (P < 0.0001). CONCLUSIONS: This is the first study to describe geographical variations in the INSPPIRE cohort, which possibly reflect variations in practice and referral patterns. The underlying reason behind the lower frequency of CP and fewer treatments in non-United States sites need to be further explored.

Pancreatic and Islet Remodeling in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Knockout Ferrets.

In cystic fibrosis (CF), there is early destruction of the exocrine pancreas, and this results in a unique form of diabetes that affects approximately half of adult CF individuals. An animal model of cystic fibrosis-related diabetes has been developed in the ferret, which progresses through phases of glycemic abnormalities because of islet remodeling during and after exocrine destruction. Herein, we quantified the pancreatic histopathological changes that occur during these phases. There was an increase in percentage ductal, fat, and islet area in CF ferrets over time compared with age-matched wild-type controls. We also quantified islet size, shape, islet cell composition, cell proliferation (Ki-67), and expression of remodeling markers (matrix metalloprotease-7, desmin, and α-smooth muscle actin). Pancreatic ducts were dilated with scattered proliferating cells and were surrounded by activated stellate cells, indicative of tissue remodeling. The timing of islet and duct proliferation, stellate cell activation, and matrix remodeling coincided with the previously published stages of glycemic crisis and inflammation. This mapping of remodeling events in the CF ferret pancreas provides insights into early changes that control glycemic intolerance and subsequent recovery during the evolution of CF pancreatic disease.