Since Dr Dorothy Andersen's first description of ‘cystic fibrosis of the pancreas’ in 1938 , pancreatic complications have been at the center of the gastrointestinal complications of cystic fibrosis. Malnutrition secondary to exocrine pancreatic insufficiency (EPI) defined cystic fibrosis until the use of pancreatic enzyme replacement therapy (PERT). Although PERT has been in use for over 200 years, EPI in cystic fibrosis remains an active area of research and clinical investigation. The permanence (or lack of permanence) of EPI has recently been called into question with new cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies. In fact, alterations in exocrine pancreatic function secondary to highly effective CFTR modulators have highlighted the precarious risk of pancreatitis in those with cystic fibrosis. Cystic fibrosis patients were once thought to be protected from pancreatitis because of extreme loss of exocrine function. However, the model of pancreatitis risk for those with CFTR mutations put forward by Ooi and Durie et al. in 2011 appears to be playing out in the era of CFTR modulators . With this comes new investigations into how to detect and monitor pancreatic fibrosis and fat deposition as complications of recurrent pancreatitis in cystic fibrosis, topics set-aside long ago as foregone conclusions. Finally, new in-vitro models are teaching us about the intricate interplay between the exocrine and endocrine pancreas, which may yield new insights into endocrine (and exocrine) insufficiency in cystic fibrosis. Basic, translational, and clinical research in the pancreatic complications of cystic fibrosis are evolving how we think about the pancreas in cystic fibrosis, not only deepening our understanding of the pathophysiology but also bringing new opportunities for diagnostic and therapeutic advances.
EXOCRINE PANCREATIC INSUFFICIENCY IN CYSTIC FIBROSIS
EPI is one of most well known complications of cystic fibrosis, with cystic fibrosis being the most common cause for EPI. Greater than 85% of cystic fibrosis patients in the CF Foundation Registry are noted to be EPI , as defined by use of PERT. Although fecal elastase-1 (FE-1) testing is the most commonly used diagnostic test to identify EPI, clinicians should remember that FE-1 values can fluctuate over time  and EPI is a clinical diagnosis, not a laboratory one. Cystic fibrosis patients may exhibit EPI, and benefit from PERT, even with FE-1 results greater than 200 μg/g stool. In Brownell et al.'s [5▪] review on ‘Growth and Nutrition Cystic Fibrosis’, the authors highlight that beyond pancreatic enzyme load, pancreatic enzyme efficacy must also be considered. Impairments in both duodenal and pancreatic bicarbonate secretion [6–8], coupled with gastric acid hypersecretion in some cystic fibrosis patients , results in an acidic intestinal luminal pH, which may impair enzyme activity and thereby contribute to malabsorption. PERT has been well established as an effective therapy for EPI, when dosed appropriately, in malnourished patients  and/or those exhibiting signs/symptoms of malabsorption [11▪]. Layer et al. [11▪]. undertook a meta-analysis of published studies on the effects of PERT on survival and quality of life in patients with EPI. They identified that while many studies showed that PERT improves fat and protein absorption and growth in cystic fibrosis patients compared with placebo, there were no studies directly assessing PERT and survival, and only one examining quality of life (in chronic pancreatitis patients). Prior studies have established a positive correlation between nutrition and growth and lung function in cystic fibrosis patients , which drives our tenacious monitoring of growth and nutrition in children with cystic fibrosis.
Exocrine pancreatic insufficiency and cystic fibrosis transmembrane conductance regulator modulators
Historically, there have been no treatments to restore pancreatic function for cystic fibrosis patients with EPI. Clinicians have been limited to managing its aftereffects. In fact, many believed that with the very early onset of EPI in many cystic fibrosis patients, EPI was irreversible. Clinical studies with ivacaftor, a highly effective CFTR potentiator, have called this dogma into question. In both the ARRIVAL and KLIMB studies [13,14▪▪], treatment of children with ivacaftor improved FE-1 measurements, some to more than 200 μg/g stool and others close to it. In the phase 3 single-arm ARRIVAL study, children 12–23 months (n ≥ 15) with at least one CFTR gating mutation received ivacaftor for 24 weeks. Mean ± standard deviation FE-1 increased from 182.2 ± 217.1 to 326.9 ± 152.1 μg/g stool (mean change: 164.7 ± 151.9 μg/g stool) (Fig. 1). In the KLIMB study, the 84-week open label ivacaftor extension of the KIWI study, 28 children were analyzed for changes in FE-1. In the original KIWI study (24-week, single arm in children 2–5 years old), mean FE-1 increased by 99.8 ± 138.4 μg/g stool after 24 weeks of ivacaftor . With the KLIMB extension, at 84 weeks, the mean increase in FE-1 was 128.8 ± 428.9 μg/g stool (Fig. 1) [14▪▪]. Prior to initiation of ivacaftor during the KIWI study, only 6% of children had a FE-1 at least 200 μg/g stool (1/17), whereas after 84 weeks of ivacaftor, 35% (6/17) had FE-1 at least 200 μg/g stool. These studies provided some of the first data to suggest that EPI in cystic fibrosis may not be permanent. Of note, there was no discussion in these studies about the presence or absence of gastrointestinal symptoms associated with EPI. The potential improvement of EPI on ivacaftor has also been noted in older children. Nichols et al.[16▪] reviewed cases of older children on long-term ivacaftor and noted significant improvements in FE-1.
Exocrine pancreatic insufficiency diagnosis by imaging
Monitoring of exocrine pancreatic function in children using indirect and direct tests has recently been reviewed by the Pancreas Committee of the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) in discussing endoscopic pancreatic function testing (ePFT) [17▪]. Beyond the stool, breath, and endoscopic tests discussed, new data has emerged examining exocrine pancreatic function in cystic fibrosis patients using ultrasound and MRI. Transabdominal ultrasound is the most common modality for assessing the pancreas in children, given it is noninvasive, low cost, and broadly available. In examining B-mode ultrasound (i.e. grayscale ultrasound) characteristics in cystic fibrosis children and adults (n = 21), Engjom et al. reported that 90% of cystic fibrosis patients with EPI (CF-PI) (by FE-1 and bicarbonate concentration on ePFT) had pancreatic hyperechogenicity, whereas 27% of exocrine pancreatic-sufficient cystic fibrosis (CF-PS) patients and 33% of healthy controls displayed pancreatic hyperechogenicity . Pfahler et al. also found increased pancreatic echogenicity in cystic fibrosis patients vs. healthy controls (56 vs. 7%, respectively), although they did not distinguish between pancreatic function status. In the former study, MRI was also performed to quantify pancreatic fat and showed that CF-PI patients had increased pancreatic fat compared with CF-PS patients . In a large population study in Western Germany that included abdominal MRI (SHIP: Study of Health in Pomerania), 139 adults with EPI were compared with 1319 individuals with normal pancreatic function and found that those with EPI had significantly higher pancreatic fat than healthy controls . In addition to B-mode ultrasound, advanced ultrasound techniques, such as shear wave elastography and contrast-enhanced ultrasound have been used to examine pancreatic function in cystic fibrosis patients. Not surprisingly, given the increased pancreatic fat content of CF-PI patients, ultrasound shear wave elastography (which measures tissue stiffness) shows decreased values in CF-PI patients compared with healthy controls . In an additional study by Engjom et al.[21▪▪], CF-PI patients displayed decreased mean capillary transit time and pancreatic blood flow compared with CF-PS and healthy patients.
MRI-based assessment of exocrine pancreatic function has been of increasing interest to pancreatologists with its potential ability to provide high-fidelity cross-sectional structural information together with organ function. The most common modality to do this is secretin-magnetic resonance cholangiopancreatography (s-MRCP). In cystic fibrosis, s-MRCP is able to distinguish CF-PI from CF-PS and healthy controls, shows good positive correlation with FE-1 (r = 0.84), and has excellent diagnostic performance in predicting EPI in cystic fibrosis patients when using an intestinal volume of less than 70 ml at 13 min postsecretin (AUROC = 0.95, sensitivity = 100%, specificity = 77%) [22▪▪]. Secretin-stimulated ultrasound also performs well in identifying EPI in cystic fibrosis patients by measuring intestinal fluid area. S-US and s-MRCP results correlate well (r = 0.79); using a postsecretin peak intestinal volume of 2.5 cm2 or area under the curve of 30 cm2 with an AUROC of 1.0 (sensitivity = 1.0, specificity = 0.96) and 0.99 (sensitivity = 1.0, specificity = 0.91) [23▪]. Therefore, although FE-1 remains the most common modality to assess EPI in cystic fibrosis patients, advanced US and MRI techniques, which provide both structural and functional data, are the new frontier in the assessment of pancreatic function (Table 1). What remains to be seen is which techniques will fare the best for monitoring changes in exocrine pancreatic function in children. Identifying modalities that can distinguish subtle changes in exocrine pancreatic function will be valuable in determining clinical effectiveness of cystic fibrosis therapies and better understanding pancreatic physiology.
PANCREATITIS IN CYSTIC FIBROSIS
Pancreatitis has historically been considered rare in cystic fibrosis because of pancreatic parenchymal loss early in infant development. However, newborn screening, advancements in genetics, and CFTR modulator therapies have all increased the proportion of cystic fibrosis patients with pancreatitis. Newborn screening helps to identify cystic fibrosis patients even before symptoms may manifest. Likewise, the introduction of expanded genetic testing and full gene sequencing within and outside of newborn screening programs have greatly increased the identification of cystic fibrosis patients with minimal to mild symptoms, especially those without EPI, who would have otherwise escaped diagnosis until later in life. This expansion in the relative number of CF-PS patients has increased the number of cystic fibrosis patients that may develop pancreatitis. Nearly a decade ago, Ooi et al. put forward a model where individuals with extreme lack of CFTR function or near-normal CFTR function are unlikely to develop pancreatitis (Fig. 2). However, as CFTR dysfunction decreases, but is not eliminated, individuals’ risk for developing pancreatitis increases. CFTR mutations have been implicated in pancreatitis pathogenesis for decades and additional recent articles have further supported this [24,25▪▪,26–28]. Recommendations and guidelines for the management of acute pancreatitis in children have been established [29▪▪,30▪] and should generally be followed for cystic fibrosis children with pancreatitis.
Pancreatitis and cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis
Similar to EPI, as ivacaftor use has become more widespread, case reports/series have emerged describing CF-PI patients beginning to have pancreatitis and cystic fibrosis patients with recurrent pancreatitis experiencing a reduction in pancreatitis episodes. Due to the time delay in highly effective CFTR modulator therapy being accessible to young children, many of these reports have been in adults, however, data from children and adolescents is increasing with greater use of these drugs in children.
Petrocheilou et al. present a case of an adolescent with CF-PI (F508del/G551D) without a prior history of acute pancreatitis who experienced restoration of pancreatic function on ivacaftor (no symptoms off PERT, only used PERT for very fatty meals). Four years after starting ivacaftor therapy, the patient developed acute epigastric abdominal pain, nausea, and elevations in both amylase (2.0 × upper limit of normal) and lipase (>3.3 × upper limit of normal), consistent with a diagnosis of acute pancreatitis. Following standard acute pancreatitis management, patient was discharged, and continued on ivacaftor with no subsequent pancreatitis episodes 2 years later . This case not only further emphasizes that EPI can improve with CFTR modulator therapy but also provides a caution to cystic fibrosis providers. Children with cystic fibrosis have a multitude of reasons to experience abdominal pain (e.g. gastroesophageal reflux disease, dysmotility, constipation, small intestinal bacterial overgrowth, distal intestinal obstruction syndrome). Pancreatitis must also be considered in the differential, not only for CF-PS patients but also for CF-PI patients on CFTR modulator therapies.
Consistent with the Ooi et al. model in Fig. 2, ivacaftor can improve the frequency of recurrent pancreatitis episodes in cystic fibrosis patients with Class III/IV residual function mutations. Recently, several case reports describe an improvement in the number of pancreatitis episodes experienced by adults treated with ivacaftor [32▪▪,33–35]. These reports involve a small number of patients (range 1–15) but provide consistent evidence that when CFTR modulators shift CFTR function high enough, the risk of pancreatitis can be reduced. But what about children, do these studies only apply to adults? The case series by Carrion et al.[32▪▪] of six patients involves two children (ages 11.5 and 13.6 years) and reports an improvement in number of pancreatitis episodes, hospitalizations, PERT use, and weight in these children, similar to that seen in the other four adults. These findings support animal studies, which have shown that treatment of mouse models of chronic pancreatitis with CFTR modulators restores CFTR expression in pancreatic ducts and reduces pancreatic inflammation . The case report by John and Rowe  describing the return of pancreatitis after stopping ivacaftor not only supports the role of ivacaftor in decreasing pancreatitis episodes but also highlights that CFTR modulator therapies are needed long-term until more permanent therapies, such as gene therapy, can be developed. Gene therapy for cystic fibrosis remains an active area of investigation [37▪▪,38▪▪,39▪,40▪▪,41]. However, to date, there have not been any published studies directing CFTR gene correction at the pancreas. Although accessibility remains a hurdle to overcome, the idea that the pancreas in cystic fibrosis is beyond help is no longer an impediment to this venture.
ENDOCRINE–EXOCRINE INTERACTIONS IN CYSTIC FIBROSIS
Cystic fibrosis-related diabetes (CFRD) is a highly prevalent complication of cystic fibrosis, occurring in up to 55% of adult men [42▪▪]. Olesen et al. identified that CFRD increases with age, occurring in 0.8% of those less than 10 years old, 9.7% in 10–19 years old, 24.1% in 20–29 years old, and 32.7% in at least 30-year-olds (between 2008 and 2013 in Europe) [42▪▪]. In a pediatric-specific epidemiology study of CFRD from 2000 to 2016, Perrem et al.[43▪] identified a CFRD prevalence of 8.5% in children 10–18 years old in Canada. Although CFRD prevalence is relatively low in children, using continuous glucose monitoring, Prentice et al.[44▪] identified that serum glucose abnormalities are common in children as young as 2–6 years old.
There has long been debate on whether CFRD is a result of primary islet dysfunction or occurs secondary to inflammation from exocrine pancreatic dysfunction. Two recent studies examining CFTR expression and function in human pancreatic islets have provided convincing evidence that CFTR is almost exclusively expressed in exocrine ductal cells. Using a combination of in-situ hybridization and immunohistochemistry, White et al.[45▪] identified that CFTR mRNA was expressed in only 0.5% of insulin-positive cells, whereas CFTR protein could not be detected in any beta cells. Shik Mun et al. also showed that CFTR protein is expressed in ductal cells, not islets. Furthermore, in developing a ‘pancreas-on-a-chip’, consisting of both human exocrine ductal cells and endocrine islets, Shik Mun et al.[46▪▪] identified that pharmacologic inhibition of CFTR function in ductal cells caused a decrease in insulin secretion from islets, likely through ductal cell to islet communication. Recent studies showing that endocrine and exocrine microcirculation are tightly intercalated [47▪▪] and that insulin levels affect exocrine acinar cell stress [48▪] provide new and compelling evidence that our historical separation of the exocrine and endocrine pancreas is flawed. Future research needs to examine the endocrine and exocrine functions of the pancreas in parallel to better understand how loss of CFTR function may affect both nutrition and diabetes in cystic fibrosis.
Pancreatic complications contribute significantly to the healthcare burden of many children with cystic fibrosis. Previously thought to be binary (CF-PI or CF-PS), in today's spectrum of CFTR mutations, the diagnosis and monitoring of pancreatic function can be complex and, based on emerging evidence, may require consideration of both exocrine and endocrine function. FE-1 measurements are not absolute or fixed. They should be considered in the context of patient symptoms and may change because of the natural history of disease and therapeutic interventions, especially CFTR modulator therapies. The toolbox to measure pancreatic function is expanding and advanced imaging may play an increasing role. Recognition of pancreatitis in cystic fibrosis is important and prompt treatment should be implemented through partnerships between gastroenterologists/pancreatologists and cystic fibrosis providers. Now, over 80 years after Dorothy Andersen's first description of the pancreatic manifestations of cystic fibrosis, pancreatic disease in cystic fibrosis children is once again at the forefront of cystic fibrosis care.
Financial support and sponsorship
Z.M.S. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (K08-DK120939), CF Foundation (SELLER16L0, SELLER19GE0), North American Pediatric Gastroenterology, Stanford Maternal Child Health Research Institute, and Stanford University, Hepatology, and Nutrition Foundation, and Stanford University.
Conflicts of interest
Z.M.S. is a member of the NASPGHAN Pancreas Committee. None of the financial support listed above contributed to or influenced the content of this manuscript.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
1. Andersen DH. Cystic fibrosis
of the pancreas
and its relation to celiac disease: a clinical and pathological study. Am J Dis Child 1938; 56:344399.
2. Ooi CY, Dorfman R, Cipolli M, et al. Type of CFTR mutation determines risk of pancreatitis
in patients with cystic fibrosis
. Gastroenterology 2011; 140:153161.
3. Cystic Fibrosis
Foundation Patient Registry 2016 Annual Data Report. Bethesda, Maryland: Cystic Fibrosis
4. O'Sullivan BP, Baker D, Leung KG, et al. Evolution of pancreatic function
during the first year in infants with cystic fibrosis
. J Pediatr 2013; 162:808.e1812.e1.
5▪. Brownell JN, Bashaw H, Stallings VA. Growth and nutrition in cystic fibrosis
. Semin Respir Crit Care Med 2019; 40:775791.
6. Pratha VS, Hogan DL, Martensson BA, et al. Identification of transport abnormalities in duodenal mucosa and duodenal enterocytes from patients with cystic fibrosis
. Gastroenterology 2000; 118:10511060.
7. Zoppi G, Shmerling DH, Gaburro D, Prader A. The electrolyte and protein contents and outputs in duodenal juice after pancreozymin and secretin stimulation in normal children and in patients with cystic fibrosis
. Acta Paediatr Scand 1970; 59:692696.
8. Gelfond D, Ma C, Semler J, Borowitz D. Intestinal pH and gastrointestinal transit profiles in cystic fibrosis
patients measured by wireless motility capsule. Dig Dis Sci 2013; 58:22752281.
9. Cox KL, Isenberg JN, Ament ME. Gastric acid hypersecretion in cystic fibrosis
. J Pediatr Gastroenterol Nutr 1982; 1:559565.
10. Guven B, Demir Mis M, Karaman K, Sahin Yasar A. Effectivity of pancreatic enzyme replacement therapy in malnourished children. J Pediatr Gastroenterol Nutr 2020; 70:e114e118.
11▪. Layer P, Kashirskaya N, Gubergrits N. Contribution of pancreatic enzyme replacement therapy to survival and quality of life in patients with pancreatic exocrine insufficiency. World J Gastroenterol 2019; 25:24302441.
12. Konstan MW, Butler SM, Wohl ME, et al. Growth and nutritional indexes in early life predict pulmonary function
in cystic fibrosis
. J Pediatr 2003; 142:624630.
13. Rosenfeld M, Wainwright CE, Higgins M, et al. ARRIVAL study group. Ivacaftor treatment of cystic fibrosis
in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study. Lancet Respir Med 2018; 6:545553.
14▪▪. Rosenfeld M, Cunningham S, Harris WT, et al. An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5years (KLIMB). J Cystic Fibrosis
15. Davies JC, Cunningham S, Harris WT, et al. Rosenfeld M, KIWI Study Group. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis
and a CFTR gating mutation (KIWI): an open-label, single-arm study. Lancet Respir Med 2016; 4:107115.
16▪. Nichols AL, Davies JC, Jones D, Carr SB. Restoration of exocrine pancreatic function
in older children with cystic fibrosis
on ivacaftor. Paediatr Respir Rev 2020; S1526-0542(20)30073-7.
17▪. Patel N, Sellers ZM, Grover A, et al. Endoscopic Pancreatic Function
Testing (ePFT) in Children: a position paper from the NASPGHAN Pancreas
Committee. J Pediatr Gastroenterol Nutr 2020; (in press).
18. Engjom T, Kavaliauskiene G, Tjora E, et al. Sonographic pancreas
echogenicity in cystic fibrosis
compared to exocrine pancreatic function
fat content at Dixon-MRI. PloS One 2018; 13:e0201019.
19. Pfahler MHC, Kratzer W, Leichsenring M, et al. Point shear wave elastography of the pancreas
in patients with cystic fibrosis
: a comparison with healthy controls. Abdom Radiol (NY) 2018; 43:23842390.
20. Kromrey ML, Friedrich N, Hoffmann RT, et al. Pancreatic steatosis is associated with impaired exocrine pancreatic function
. Invest Radiol 2019; 54:403408.
21▪▪. Engjom T, Nylund K, Erchinger F, et al. Contrast-enhanced ultrasonography of the pancreas
shows impaired perfusion in pancreas
insufficient cystic fibrosis
patients. BMC Med Imaging
22▪▪. Engjom T, Tjora E, Erchinger F, et al. Secretin-stimulated magnetic resonance imaging
reveals variable diagnostic accuracy according to etiology in pancreatic disease. Pancreas
23▪. Engjom T, Tjora E, Wathle G, et al. Secretin-stimulated ultrasound estimation of pancreatic secretion in cystic fibrosis
validated by magnetic resonance imaging
. Eur Radiol 2018; 28:14951503.
24. Nabi Z, Talukdar R, Venkata R, et al. Genetic evaluation of children with idiopathic recurrent acute pancreatitis
. Dig Dis Sci 2020.
25▪▪. Baldwin C, Zerofsky M, Sathe M, et al. Acute recurrent and chronic pancreatitis
as initial manifestations of cystic fibrosis
and cystic fibrosis
transmembrane conductance regulator-related disorders. Pancreas
26. Abu-El-Haija M, Valencia CA, Hornung L, et al. Genetic variants in acute, acute recurrent and chronic pancreatitis
affect the progression of disease in children. Pancreatology 2019; 19:535540.
27. Iso M, Suzuki M, Yanagi K, et al. The CFTR gene variants in Japanese children with idiopathic pancreatitis
. Hum Genome Var 2019; 6:17.
28. Zou WB, Tang XY, Zhou DZ, et al. SPINK1, PRSS1, CTRC, and CFTR genotypes influence disease onset and clinical outcomes in chronic pancreatitis
. Clin Translat Gastroenterol 2018; 9:204.
29▪▪. Abu-El-Haija M, Kumar S, Quiros JA, et al. Management of acute pancreatitis
in the pediatric population: a clinical report from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Pancreas
Committee. J Pediatr Gastroenterol Nutr 2018; 66:159176.
30▪. Sellers ZM, Dike C, Zhang KY, et al. A unified treatment algorithm and admission order set for pediatric acute pancreatitis
. J Pediatr Gastroenterol Nutr 2019; 68:e109e111.
31. Petrocheilou A, Kaditis AG, Loukou I. Pancreatitis
in a patient with cystic fibrosis
taking ivacaftor. Children (Basel) 2020; 7:6.
32▪▪. Carrion A, Borowitz DS, Freedman SD, et al. Reduction of recurrence risk of pancreatitis
in cystic fibrosis
with ivacaftor: case series. J Pediatr Gastroenterol Nutr 2018; 66:451454.
33. Kounis I, Levy P, Rebours V. Ivacaftor CFTR potentiator therapy is efficient for pancreatic manifestations in cystic fibrosis
. Am J Gastroenterol 2018; 113:10581059.
34. Akshintala VS, Kamal A, Faghih M, et al. Cystic fibrosis
transmembrane conductance regulator modulators reduce the risk of recurrent acute pancreatitis
among adult patients with pancreas
sufficient cystic fibrosis
. Pancreatology 2019; 19:10231026.
35. Johns JD, Rowe SM. The effect of CFTR modulators on a cystic fibrosis
patient presenting with recurrent pancreatitis
in the absence of respiratory symptoms: a case report. BMC Gastroenterol 2019; 19:123.
36. Zeng M, Szymczak M, Ahuja M, et al. Restoration of CFTR activity in ducts rescues acinar cell function
and reduces inflammation in pancreatic and salivary glands of mice. Gastroenterology 2017; 153:11481159.
37▪▪. Erwood S, Laselva O, Bily TMI, et al. Allele-specific prevention of nonsense-mediated decay in cystic fibrosis
using homology-independent genome editing. Mol Ther Methods Clin Dev 2020; 17:11181128.
38▪▪. Suzuki S, Crane AM, Anirudhan V, et al. Highly efficient gene editing of cystic fibrosis
patient-derived airway basal cells results in functional CFTR correction. Mol Ther 2020; 28:168495.
39▪. Fleischer A, Vallejo-Diez S, Martin-Fernandez JM, et al. iPSC-derived intestinal organoids from cystic fibrosis
patients acquire CFTR activity upon TALEN-mediated repair of the p.F508del mutation. Mol Ther Methods Clin Dev 2020; 17:858870.
40▪▪. Vaidyanathan S, Salahudeen AA, Sellers ZM, et al. High-efficiency, selection-free gene repair in airway stem cells from cystic fibrosis
Patients rescues CFTR function
in differentiated epithelia. Cell Stem Cell 2020; 26:161.e4-171.e4.
41. Maule G, Casini A, Montagna C, et al. Allele specific repair of splicing mutations in cystic fibrosis
through AsCas12a genome editing. Nat Commun 2019; 10:3556.
42▪▪. Olesen HV, Drevinek P, Gulmans VA, et al. Cystic fibrosis
related diabetes in Europe: prevalence, risk factors and outcome. J cystic fibrosis
43▪. Perrem L, Stanojevic S, Solomon M, et al. Incidence and risk factors of paediatric cystic fibrosis
-related diabetes. J Cystic Fibrosis
44▪. Prentice BJ, Ooi CY, Verge CF, et al. Glucose abnormalities detected by continuous glucose monitoring are common in young children with Cystic Fibrosis
. J Cyst Fibrosis 2020; S1569-1993(20)30057-6.
45▪. White MG, Maheshwari RR, Anderson SJ, et al. In situ analysis reveals that CFTR is expressed in only a small minority of beta-cells in normal adult human pancreas
. J Clin Endocrinol Metab 2020; 105:136674.
46▪▪. Shik Mun K, Arora K, Huang Y, et al. Patient-derived pancreas
-on-a-chip to model cystic fibrosis
-related disorders. Nat Commun 2019; 10:3124.
47▪▪. Dybala MP, Kuznetsov A, Motobu M, et al. Integrated pancreatic blood flow: bi-directional microcirculation between endocrine and exocrine pancreas
. Diabetes 2020; 69:143950.
48▪. Yatchenko Y, Horwitz A, Birk R. Endocrine and exocrine pancreas
pathologies crosstalk: Insulin regulates the unfolded protein response in pancreatic exocrine acinar cells. Exp Cell Res 2019; 375:2835.