Cystic Fibrosis Of Pancreas Research Articles

EPS4.04 A stitch in time saves nine – abnormal glucose tolerance in patients with cystic fibrosis: systematic review and meta-analysis

Objectives: Basic science results suggest that abnormalities of the endocrine pancreas in cystic fibrosis (CF) occur earlier than was believed so far. All stages of the spectrum of glucose metabolism disorders are associated with increased morbidity and mortality which could be reduced by early recognition and treatment. However, screening for abnormal glucose tolerance (AGT) is recommended only from the age of 10 according to the actual guidelines. We conducted a systematic review and meta-analysis on the prevalence of abnormal glucose tolerance in patients with CF with a focus on children under 10 years of age.

Pancreas and islet morphology in cystic fibrosis: clues to the etiology of cystic fibrosis-related diabetes.

Cystic fibrosis (CF) is a multi-organ disease caused by loss-of-function mutations in CFTR (which encodes the CF transmembrane conductance regulator ion channel). Cystic fibrosis related diabetes (CFRD) occurs in 40-50% of adults with CF and is associated with significantly increased morbidity and mortality. CFRD arises from insufficient insulin release from β cells in the pancreatic islet, but the mechanisms underlying the loss of β cell function remain understudied. Widespread pathological changes in the CF pancreas provide clues to these mechanisms. The exocrine pancreas is the epicenter of pancreas pathology in CF, with ductal pathology being the initiating event. Loss of CFTR function results in ductal plugging and subsequent obliteration. This in turn leads to destruction of acinar cells, fibrosis and fatty replacement. Despite this adverse environment, islets remain relatively well preserved. However, islet composition and arrangement are abnormal, including a modest decrease in β cells and an increase in α, δ and γ cell abundance. The small amount of available data suggest that substantial loss of pancreatic/islet microvasculature, autonomic nerve fibers and intra-islet macrophages occur. Conversely, T-cell infiltration is increased and, in CFRD, islet amyloid deposition is a frequent occurrence. Together, these pathological changes clearly demonstrate that CF is a disease of the pancreas/islet microenvironment. Any or all of these changes are likely to have a dramatic effect on the β cell, which relies on positive signals from all of these neighboring cell types for its normal function and survival. A thorough characterization of the CF pancreas microenvironment is needed to develop better therapies to treat, and ultimately prevent CFRD.

The Exocrine Pancreas in Cystic Fibrosis in the Era of CFTR Modulation: A Mini Review.

Cystic fibrosis (CF) is a common disorder of autosomal recessive inheritance, that once conferred a life expectancy of only a few months. Over recent years, significant advances have been made to CF therapeutic approaches, changing the face of the disease, and facilitating the partial restoration of pancreatic function. This mini review summarizes the current landscape of exocrine pancreatic management in CF and explores areas for future direction and development.

13-OR: Cystic Fibrosis Donors Exhibit Striking Decrease in Pancreatic Islet and Exocrine Capillaries

Glucose intolerance and insulin deficiency are common features of cystic fibrosis (CF) , with nearly half of adult CF patients developing CF-related diabetes (CFRD) , but the underlying pathophysiology remains poorly understood. Extensive destruction of the exocrine pancreas occurs in most CF patients. However, islets are still readily detectable, suggesting β cell loss is not the major driver of impaired insulin release. Islets are normally highly vascularized, and islet capillaries are the source of key growth factors that maintain β cell health and function. Islet capillary morphology is altered in type 1 and type 2 diabetes, with increased capillary density and/or vessel thickening being observed. In the present study we aimed to determine whether islet capillaries are also disrupted in CF/CFRD. Pancreas sections (8 control and 8 CF/CFRD, age-matched) were stained for CD31, a marker of vascular endothelial cells. Islets in microscopy images were manually identified (17.8±2.8[SEM] per sample) and CD31-positive area within islet and exocrine was quantified. Mean islet cross-sectional area did not significantly differ between CF and non-CF pancreas specimens. CD31 positive area, expressed as a fraction of islet area, was significantly decreased in CF pancreas specimens (2.8±0.9% vs. 6.1±1.2%; p=0.05) . Islet capillary density (the number of CD31+ objects normalized to islet area) was also decreased (0.88±0.17x103/μm2 vs. 3.8±0.57x103/μm2; p=0.0004) , as was exocrine tissue CD31 positive area (0.17±0.03% vs. 1.5±0.23%; p<0.0001) . Our data demonstrate a significant deficit in islet and pancreatic vascularity in CF/CFRD. This contrasts markedly with the increase in islet capillary density seen in both T1D and T2D and underscores the presence of distinct features of islet morphology that characterize CF. Given that islet capillaries support β-cell function and survival, their loss likely contributes to impaired β-cell function. Disclosure J.J.Castillo: None. A.Aplin: None. R.Akter: None. R.L.Hull-meichle: Research Support; Casma Therapeutics. Funding Cystic Fibrosis Foundation Fellowship (CASTIL20F0)

VIP reduction in the pancreas of F508del homozygous CF mice and early signs of Cystic Fibrosis Related Diabetes (CFRD)

Vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide with potent anti-inflammatory, bronchodilatory and immunomodulatory functions, is secreted by intrinsic neurons innervating all exocrine glands, including the pancreas, in which it exerts a regulatory function in the secretion of insulin and glucagon. Cystic fibrosis-related diabetes (CFRD) is the most common co-morbidity associated with cystic fibrosis (CF), impacting approximately 50% of adult patients. We recently demonstrated a 50% reduction of VIP abundance in the lungs, duodenum and sweat glands of C57Bl/6 CF mice homozygous for the F508del-CFTR disease-causing mutation. VIP deficiency resulted from a reduction in VIPergic and cholinergic innervation, starting before signs of CF disease were observed. As VIP functions as a neuromodulator with insulinotropic effect on pancreatic beta cells, we sought to study changes in VIP in the pancreas of CF mice. Our goal was to examine VIP content and VIPergic innervation in the pancreas of 8- and 17-week-old F508del-CFTR homozygous mice and to determine whether changes in VIP levels would contribute to CFRD development. Our data showed that a decreased amount of VIP and reduced innervation are found in CF mice pancreas, and that these mice also exhibited reduced insulin secretion, up-regulation of glucagon production and high random blood glucose levels compared to same-age wild-type mice. We propose that low level of VIP, due to reduced innervation of the CF pancreas and starting at an early disease stage, contributes to changes in insulin and glucagon secretion that can lead to CFRD development.

1842-P: Enhanced TGF-ß1 Signaling in the Ducts of Cystic Fibrosis Pancreas Increases Basal Insulin Secretion by Islets

Cystic fibrosis (CF) is a multi-organ disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR protein is most highly expressed in pancreatic ductal epithelium, where loss of its function leads to ductal plugging, acinar destruction, and eventual diabetes. We hypothesize that exocrine pancreas remodeling in CF alters ductal paracrine signals to the endocrine pancreas. To test this hypothesis, we established primary ductal epithelium grown at an air-liquid interface (ALI) from WT and CFTR-KO ferret pancreas. Carbachol or IBMX/Forskolin (I/F) stimulated basolateral and apical secretions were analyzed for differentially secreted proteins using quantitative mass spectroscopy. Upon carbachol secretion 39 apical and 15 basolateral proteins were differentially secreted (P<0.05) by CFTR-KO ducts. Similarly, 26 and 6 differentially secreted proteins (P<0.05) were identified from I/F stimulated apical and basolateral secretions, respectively. TGF-β1 was one of the top upstream regulators of the differentially secreted proteins, P=5.02E-13 by Ingenuity Pathway Analysis. Single molecule fluorescence in situ hybridization of TGF-β1 mRNA on CFTR-KO and WT ferret pancreas indicated increased expression in CFTR-KO ducts compared to age matched controls. Likewise, expression of IGFBP7, a TGF-β1 signaling target, was augmented in fibroblasts surrounding pancreatic ducts and also in endocrine cells in CFTR-KO pancreas relative to controls. In cultured WT ferret islets, IGFBP7 treatment enhanced basal insulin secretion (2-fold, P<0.05) and attenuated glucose stimulated insulin secretion. This IGFBP7-dependent insulin secretion phenotype was similar to that observed in cultured CFTR-KO islets, suggesting TGF-β1 signaling may be partly responsible for altered insulin secretion in CF. Disclosure P. Rotti: None. I. Apak-Evans: None. Y. OMalley: None. A. Norris: None. A. Uc: None. J. Engelhardt: None. Funding National Institutes of Health

An Increase in Chromogranin A-Positive, Hormone-Negative Endocrine Cells in Pancreas in Cystic Fibrosis.

We sought to establish whether an increase in chromogranin A-positive, hormone-negative (CPHN) endocrine cells occurs in the pancreas of patients with cystic fibrosis (CF), as potential evidence of neogenesis.Pancreata were obtained at autopsy from nondiabetic patients with CF (n = 12) and age-matched nondiabetic control subject (CS) individuals without CF (n = 12). In addition, pancreas from three diabetic patients with CF was obtained. Pancreas sections were stained for chromogranin A, insulin, and a cocktail of glucagon, somatostatin, pancreatic polypeptide, and ghrelin and evaluated for the frequency of CPHN cells.There was a higher frequency of CPHN cells in islets of the patients with CF compared with the CS group. Moreover, CPHN cells occurring as single cells or clusters scattered in the exocrine pancreas were also more frequent in patients with CF.The increased frequency of CPHN cells in pancreas of patients with CF may indicate an attempt at endocrine cell regeneration.

EPS3.4 Functional and conventional MRI of the pancreas in cystic fibrosis – validating sonographic findings

EPS3.4 Functional and conventional MRI of the pancreas in cystic fibrosis – validating sonographic findings

Under Utilization of Pancreas Transplants in Cystic Fibrosis Recipients in the United Network Organ Sharing (UNOS) Data 1987-2014.

Despite a high prevalence of pancreatic endocrine and exocrine insufficiency in cystic fibrosis (CF), pancreas transplantation is rarely reported. United Network for Organ Sharing (UNOS) data were used to examine utilization of pancreas transplant and posttransplant outcomes in CF patients. Between 1987-2014, CF patients (N = 4600) underwent 17 liver-pancreas, three lung-pancreas, one liver-lung pancreas, four kidney-pancreas, and three pancreas-only transplants. Of the 303 CF patients who received liver transplantation, 20% had CF-related diabetes (CFRD) before transplantation, and nine of those received a liver-pancreas transplant. Of 4241 CF patients who underwent lung transplantation, 33% had CFRD before transplantation, and three of those received a pancreas transplant. Of 49 CF patients who received a liver-lung transplant, 57% had CFRD before transplantation and one received a pancreas transplant. Posttransplantation diabetes developed in 7% of CF pancreas transplant recipients versus 24% of CF liver and 29% of CF lung recipients. UNOS has no data on pancreas exocrine insufficiency. Two-year posttransplantation survival was 88% after liver-pancreas transplant, 33% after lung-pancreas transplant, and 100% after pancreas-kidney and pancreas-only transplants. Diabetes is common pretransplantation and posttransplantation in CF solid organ transplant recipients, but pancreas transplantation remains rare. Further consideration of pancreas transplant in CF patients undergoing other solid organ transplant may be warranted.

239 Parenchymal and functional ultrasonographic imaging of the pancreas in cystic fibrosis correlates with exocrine pancreatic function

237 A new endoscopic short test for exocrine pancreatic function in cystic fibrosis T. Engjom1,2, B.N. Laerum3, F. Erchinger2,4, E. Tjora5,6, O.H. Gilja1,2,7, G. Dimcevski1,2. 1Haukeland University Hospital, Section for Gastroenterology, Bergen, Norway; 2University of Bergen, Institute of Medicine, Bergen, Norway; 3Haukeland University Hospital, Department of Thoracic Medicine, Bergen, Norway; 4Voss Hospital, Department of Medicine, Voss, Norway; 5Haukeland University Hospital, Department of Paediatry, Bergen, Norway; 6University of Bergen, Institute for Clinical Medicine, Bergen, Norway; 7Haukeland University Hospital, National Centre for Ultrasound in Gastroenterology, Bergen, Norway

Cystic fibrosis of pancreas and nephrotic syndrome: a rare association

Cystic fibrosis (CF) is a genetic disease with autosomal recessive inheritance and is common in Caucasian people. The prevalence of this disease is between 1/2,000 and 1/3,500 live births, and the incidence varies between populations. Although the CF transmembrane conductance regulator gene is expressed in the kidneys, renal involvement is rare. With advances in the treatment of CF, life expectancy has increased, and some previously unobserved disease associations are now seen in patients with CF. It is important to follow patients with CF for possible abnormalities that may accompany CF. In this paper, we present two rare cases of CF accompanied by nephrotic syndrome.

Kwashiorkor e distúrbio de coagulação: apresentação atípica de fibrose cística

OBJETIVO: Enfatizar a apresentação clínica precoce da fibrose cística (FC) em lactente com Kwashiorkor e distúrbio de coagulação, decorrente de hipovitaminose K. DESCRIÇÃO DO CASO: Paciente com três meses e meio, sexo feminino, nascida a termo, peso de 2655g, estatura de 46cm, foi encaminhada para investigação de lesões perineais associadas à monilíase de difícil controle, refratária a diversos antifúngicos e corticoides. Quadro geral caracterizado por baixo ganho ponderal, edema e diarreia. Admissão hospitalar para investigação com hipótese diagnóstica de Kwashiorkor de origem primária ou secundária. Paciente mantida em aleitamento materno exclusivo, sendo observadas perda ponderal e persistência da diarreia. Na internação, foi iniciado tratamento de infecção do trato urinário. A paciente evoluiu com hemorragia digestiva alta e sangramento pela flebotomia em safena direita, sendo identificada coagulopatia responsiva à vitamina K e plasma fresco congelado. Na evolução, foi confirmada esteatorreia e hipoalbuminemia; as sorologias para sífilis, toxoplasmose, mononucleose, citomegalovírus, rubéola, HIV e hepatite B, apresentaram resultado negativo e a pesquisa da mutação ∆F508 heterozigoto para FC foi positiva. A paciente apresentou piora do estado geral com sinais de sepse, evoluindo para óbito. O laudo necroscópico evidenciou elementos característicos de choque séptico com infecção pulmonar, sinais acentuados de desnutrição e fibrose cística do pâncreas. COMENTÁRIOS: A FC pode manifestar-se com quadro de Kwashiorkor e distúrbio de coagulação por deficiência de vitamina K. Os profissionais de saúde devem estar atentos à possibilidade de FC no diagnóstico diferencial dessa situação.

MRI appearance of the pancreas in patients with cystic fibrosis: a comparison of pancreas volume in diabetic and non-diabetic patients

We investigated differences in the volume of the pancreas in cystic fibrosis (CF) patients with and without diabetes using MRI to study the natural history of CF-related diabetes (CFRD). We investigated 29 pancreas-insufficient adult CF patients, 13 with CFRD and 16 without diabetes. Patients with CFRD were receiving insulin therapy at the time of study. None of the non-diabetic CF patients had evidence of impaired glucose tolerance. Pancreas volume was estimated by MRI scans using T₁ weighted fat-suppression sequences and assessed by an examiner who was unaware of the patients' diabetes status. Pancreas volume of CF patients was measured and subsequently compared with that of non-CF age-matched Type 1 diabetes (T1DM) patients and healthy controls previously investigated. The two CF groups were matched for age and gender. There were no differences in spirometry values, body mass index or pancreatic exocrine function. The pancreas was visible by MRI in only 3 of 13 (23.1%) patients with CFRD and in 5 of 16 (31.3%) patients without diabetes (p-value = 0.7). In total, the pancreas was not detected by MRI as an anatomical entity in 21 of 29 (72.4%) CF patients, irrespective of their diabetes status. When comparing the four study groups, the pancreas was significantly smaller in CF patients than in T1DM patients and healthy controls.

The changing face of the exocrine pancreas in cystic fibrosis: pancreatic sufficiency, pancreatitis and genotype

(Table is included in full-text article.)Cystic fibrosis (CF) is the most frequent cause of exocrine pancreatic insufficiency in childhood. The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes CFTR protein that functions as cyclic AMP-dependent chloride channel allowing the passage of anions and secondarily water into the lumen of pancreatic ducts. Luminal chlorides are exchanged for bicarbonates. The lack of CFTR channel or its disrupted function (being the consequence of CFTR gene mutations) results in reduced volume of more acidic secretion. It has been suggested that such a situation leads to the precipitation of highly concentrated protein-containing secretion with obstruction and organ damage. The intensity of this process determines the progression of the disease. Steatorrhea is the significant symptom of classical form of CF. Residual pancreatic secretion in a subset of patients, however, allows for normal lipid digestion and absorption. Previous cross-sectional clinical studies estimated that about 85-90% of CF patients in preschool, school and older age are pancreatic insufficient. More frequent detection of mild and nonclassic forms of CF leads to higher frequency of pancreatic sufficiency (PS). The potential decline of exocrine pancreatic function, however, should be always considered. All PS patients with at least one severe or unknown CFTR mutation should be longitudinally assessed for the progression of pancreatic dysfunction. Recurrent acute and chronic pancreatitis is not a rare clinical condition in PS patients with PS: it might be the presenting symptom, even preceding CF diagnosis by several years. Potential appearance of this complication in individuals with pancreatic insufficiency demands elucidation.

The changing face of the exocrine pancreas in cystic fibrosis: the correlation between pancreatic status, pancreatitis and cystic fibrosis genotype

The aims of this study were to determine the current pancreatic status of the entire cystic fibrosis (CF) population of Israel, to analyze the clinical characteristics of the pancreatic sufficient (PS) patients, and to characterize the correlation between pancreatic status, pancreatitis, and CF genotype. The Israeli CF database includes 505 patients. These patients were defined as being PS or insufficient according to their fecal pancreatic elastase level or by coefficient fat absorption findings. Mutations were categorized as severe (DeltaF508, W1282X, G542X, S549R, N1303K, Q359K/T360K, 405+1G, and 1717) or mild/variable (3849+10 kb, D1152H, G85E, I1234V, R334W, and 5T) based on disease severity in patients carrying these mutations. Age at diagnosis, presenting symptoms, sweat-chloride concentrations, occurrence of pancreatitis, presence of diabetes, and liver disease were recorded. One hundred and thirty-nine (27.5%) of the CF patients were PS. None carried two mutations associated with severe disease. Over one third (34%) had normal or borderline sweat tests; 20 of these 139 patients had pancreatitis (14.3%) but none of the 366 pancreatic insufficient patients had it. Four initially PS patients became pancreatic insufficient: conversion followed several events of pancreatitis in three of them. Nasal potential differences were all pathological in 35 tested PS patients. None had either diabetes or liver disease. A substantial number of CF patients are PS. All of them carry at least one mild mutation enabling production of a sufficient amount of normal mRNA to maintain exocrine pancreatic function. Pancreatitis occurs only in CF patients who are PS. These patients are at risk of progressing to pancreatic insufficiency.

Caerulein-induced acute pancreatitis in mice that constitutively overexpress Reg/PAPgenes

BackgroundThe cystic fibrosis (CF) mouse pancreas has constitutively elevated expression of the Reg/PAP cell stress genes (60-fold greater Reg3α, and 10-fold greater PAP/Reg3β and Reg3γ). These genes are suggested to be involved in protection or recovery from pancreatic injury.MethodsTo test this idea the supramaximal caerulein model was used to induce acute pancreatitis in wild type and CF mice. Serum amylase, pancreatic water content (as a measure of edema), pancreatic myeloperoxidase activity, and Reg/PAP expression were quantified.ResultsIn both wild type and CF mice caerulein induced similar elevations in serum amylase (maximal at 12 h), pancreatic edema (maximal at 7 h), and pancreatic myeloperoxidase activity (MPO, a marker of neutrophil infiltration; maximal at 7 h). By immunohistochemistry, Reg3α was strongly expressed in the untreated CF pancreas but not in wild type. During pancreatitis, Reg3α was intensely expressed in foci of inflamed tissue in both wild type and CF.ConclusionThese data demonstrate that the severity of caerulein-induced pancreatitis is not ameliorated in the CF mouse even though the Reg/PAP stress genes are already highly upregulated. While Reg/PAP may be protective they may also have a negative effect during pancreatitis due to their anti-apoptotic activity, which has been shown to increase the severity of pancreatitis.

Focal fatty sparing of the pancreatic head in cystic fibrosis: CT findings.

The most common imaging appearance of the pancreas in cystic fibrosis is diffuse, complete fatty replacement. We present a case of complete fatty replacement of the pancreatic body and tail with total sparing of the pancreatic head. To our knowledge, this pattern of fatty sparing and its associated computed tomographic appearance have not been previously reported in cystic fibrosis.

The pancreas in cystic fibrosis.

The pancreas secretes a bicarbonate-rich fluid containing digestive enzymes via the ampulla of Vater into the duodenum. Defective secretion leads to maldigestion of fat and protein with increased faecal losses. Cystic fibrosis (CF) is the major cause of pancreatic exocrine failure in childhood, whereas pancreatic insufficiency in adults is commonly associated with chronic pancreatitis and alcohol ingestion. In cystic fibrosis, pancreatic function correlates with genotype; pancreatic-sufficient (PS) patients have a milder course of respiratory disease, improved survival and lower mean sweat chloride concentrations than those with pancreatic insufficiency. Recent observations suggest that mutant CF alleles are over-represented in patients with chronic pancreatitis. Few show evidence of sino-pulmonary disease or high sweat electrolyte concentrations.

Changes in the exocrine pancreas secondary to altered small intestinal function in the CF mouse.

The exocrine pancreas of the cystic fibrosis (CF) mouse (cftr(m1UNC)) is only mildly affected compared with the human disease, providing a useful model to study alterations in exocrine function. The CF mouse pancreas has approximately 50% of normal amylase levels and approximately 200% normal Muclin levels, the major sulfated glycoprotein of the pancreas. Protein biosynthetic rates and mRNA levels for amylase were not altered in CF compared with normal mice, and increases in Muclin biosynthesis and mRNA paralleled the increased protein content. Stimulated pancreatic amylase secretion in vitro and in vivo tended to be increased in CF mice but was not statistically significant compared with normal mice. We show for the first time that the CF mouse duodenum is abnormally acidic (normal intestinal pH = 6.47 +/- 0.05; CF intestinal pH = 6.15 +/- 0.07) and hypothesize that this may result in increased signaling to the exocrine pancreas. There were significant increases in CF intestinal mRNA levels for secretin (310% of normal, P < 0.001) and vasoactive intestinal peptide (148% of normal, P < 0.05). Furthermore, CF pancreatic cAMP levels were 147% of normal (P < 0.01). These data suggest that the CF pancreas may be chronically stimulated by cAMP-mediated signals, which in turn may exacerbate protein plugging in the acinar/ductal lumen, believed to be the primary cause of destruction of the pancreas in CF.

Hepatobiliary and Pancreatic Manifestations of Cystic Fibrosis: MR Imaging Appearances

Magnetic resonance (MR) imaging and MR cholangiopancreatography are useful, noninvasive techniques for the assessment of pancreatic and hepatobiliary complications in cystic fibrosis. Abnormalities of the pancreas in cystic fibrosis are typically characterized by fat deposition, which has increased signal intensity on T1-weighted MR images, and pancreatic fibrosis, which has low signal intensity on both T1- and T2-weighted images. Pancreatic cysts are a relatively common finding; these cysts are typically quite small but are well demonstrated at MR imaging and MR cholangiopancreatography. Pancreatic duct abnormalities are also occasionally seen. Hepatic manifestations range from hepatomegaly and diffuse fatty infiltration to severe cirrhosis with fibrotic change, regenerative nodules, and portal hypertension. Splenomegaly is often characterized by siderotic nodules that manifest as multiple focal areas of abnormal low signal intensity within the spleen. Biliary manifestations include cholelithiasis, stricturization, and narrowing or dilatation of intra- and extrahepatic bile ducts. Gallbladder abnormalities including microgallbladder are also readily demonstrated. MR cholangiopancreatography can be used to help determine the presence and severity of biliary complications without resorting to more invasive procedures and, in conjunction with MR imaging, may prove useful in the assessment of patients with cystic fibrosis who present with abdominal symptoms that suggest hepatobiliary involvement.