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GASTROENTEROLOGY AND NUTRITION: Edited by Bradley Barth

Pancreatic complications in children with cystic fibrosis

Sellers, Zachary M.

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Current Opinion in Pediatrics: October 2020 - Volume 32 - Issue 5 - p 661-667
doi: 10.1097/MOP.0000000000000934
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Abstract

INTRODUCTION

Since Dr Dorothy Andersen's first description of ‘cystic fibrosis of the pancreas’ in 1938 [1], 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 [2]. 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. 

Box 1
Box 1:
no caption available

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 [3], 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 [4] 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 [9], 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 [10] 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 [12], 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 [15]. 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.

FIGURE 1
FIGURE 1:
Children treated with the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor experience an increase in exocrine pancreatic function as measured by FE-1. Summary of data from the ARRIVAL, KIWI, and KLIMB clinical trials. The mean (line) absolute increase in FE-1 before and after ivacaftor treatment is shown. Box upper and lower limit lines represent 95% confidence intervals. Children in the ARRIVAL, KIWI, and KLIMB studies were treated with ivacaftor for 24, 24, and 84 weeks, respectively. FE-1, fecal elastase-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 [18]. Pfahler et al.[19] 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 [18]. 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 [20]. 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 [19]. 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.

Table 1
Table 1:
Comparison of imaging modalities to assess exocrine pancreatic function with fecal elastase-1 testing

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.[2] 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.

FIGURE 2
FIGURE 2:
Pancreatitis risk model based on degree of pancreatic function. Ooi et al. put forward a conceptual model, which described that individuals with none/minimal or near-normal CFTR function are unlikely to develop pancreatitis. However, those with residual CFTR function, even if impaired, are at risk for pancreatitis. Reproduced with permission from [2]. CTFR, cystic fibrosis transmembrane conductance regulator.

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 [31]. 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 [36]. The case report by John and Rowe [35] 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.

CONCLUSION

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.

Acknowledgements

None.

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:

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Keywords:

cystic fibrosis; function; imaging; pancreas; pancreatitis

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