1. Introduction

1.1. Esophagus and Stomach

1.1.1. GERD and Foregut Dysmotility

Gastrointestinal reflux disease (GERD) is a common extrapulmonary manifestation in CF. Several studies have suggested that GERD in CF leads to more severe pulmonary manifestations, though the interplay is complex (8-12). Multiple underlying mechanical and chemical factors have been implicated in the pathogenesis of GERD in PwCF, including increased transient lower esophageal sphincter (LES) relaxation, increased intra-abdominal pressure from coughing, delayed gastric emptying, decreased basal LES tone, lung hyperinflation effects on the diaphragm, and medication effects (Figure 1) (10, 13-16). Given the lack of specific guidelines for GERD in CF, the diagnostic and therapeutic strategy for GERD in PwCF does not differ from the general population and includes behavioral modifications, dietary changes, medications, and procedures targeting acid production (17).

GI dysmotility is likely a key factor in the GI manifestations of CF with complex pathophysiology and symptoms that overlap with GERD and dyspepsia. Disruptions in motility are thought to arise from defective epithelial CFTR in the neuromuscular complex acting as a primary insult and leading to altered intestinal myenteric ganglia and abnormal ileal smooth muscle function. Secondary causes of GI dysmotility include decreased bicarbonate and mucoviscidosis from pancreatic insufficiency (PI), fat malabsorption due to poor micelle formation, gut inflammation due to dysbiosis, and hormonal dysregulation (18). This is further exacerbated by frequent use of anti-cholinergic medications and opiates. Wireless motility capsules have been used to study GI transit profiles in CF and demonstrated significant delay in small bowel transit time without a compensatory increase in whole gut transit time and deficient buffering capacity required to neutralize gastric acid in the proximal small bowel (18, 19). Gastroparesis is a common dysmotility diagnosis in CF that can lead to reduced oral intake, nutritional deficiencies, low body mass index, poor quality of life, and variable response to pancreatic enzyme replacement therapy (PERT). The use of gastric emptying scintigraphy in CF is an area of debate due to inconsistent findings and lack of reproducibility (18). Specific guidelines for the management of gastroparesis in CF have not been established.

Figure 1. Mechanical and chemical factors in the pathogenesis of GERD in PwCF..

Figure 1. Mechanical and chemical factors in the pathogenesis of GERD in PwCF..

Pediatrics

In children with CF (CwCF), GERD is the most common GI manifestation. GERD in children can be exacerbated by the risk factors in Figure 1 and by excessive coughing and use of vest therapy for pulmonary toileting (10). About two-thirds of children are asymptomatic, while others manifest symptoms of heartburn, abdominal pain and vomiting. Refusal to eat can be a subtle sign of underlying GERD. Higher incidence of aspiration pneumonia is noted in children with symptomatic GERD (20). It is essential to treat GERD effectively given the possible association with poor pulmonary outcomes (21) Unrecognized GERD can limit caloric intake contributing to malnutrition particularly in children, which could be significant for CwCF with higher caloric needs. GERD is a clinical diagnosis, although pH Multichannel Intraluminal Impedance (MII) studies could provide objective evidence. ​In patients with persistent symptoms despite proton pump inhibitors (PPI) therapy or red flags such as hematemesis, poor growth, esophagogastroduodenoscopy (EGD) should be performed to evaluate for mucosal pathology. Dysmotility in CF affects various portions of GI tract, leading to reflux, dyspepsia, gastroparesis and constipation and can also contribute to refractory reflux symptoms (21). A systematic review showed a pooled prevalence of gastroparesis of 38% in CwCF, higher than the general pediatric population (22).

Lifestyle modifications such as a healthy diet, avoiding spicy food, limiting carbonated/sugary/caffeinated beverages are emphasized. Behavioral changes such as avoiding head-down postural drainage in infants can also help to minimze reflux and aspiration. Commonly used acid reducing medications, in children are histamine receptor 2 antagonists (H2-RA) and PPI. Most children remain on acid suppressive therapy long-term, with attempts to wean if asymptomatic and meeting appropriate growth parameters. PPIs are considered to improve efficacy of PERT and used as an adjuvant in management of PI although its true efficacy in modern PERT use is unknown. Prokinetic agents such as metoclopramide, domperidone, and macrolide antibiotics have low efficacy in treating reflux but are commonly used in treating gastroparesis in children (23). Azithromycin, a potent anti-inflammatory and pro-kinetic agent, is used to improve gastric motility, although studies have shown it reduces GERD and bile aspiration (specifically after transplantation) in a small subset of CF (24). There is controversial data regarding efficacy of fundoplication in CwCF (25, 26), although it may be considered in medically refractory GERD with comorbidities such as frequent pulmonary exacerbation, recurrent aspiration pneumonia and malnutrition. Apart from reflux esophagitis, other complications such as Barrett’s esophagus and esophageal cancers are rarely seen in the pediatric population.

Adults

In adults with CF (AwCF), there is an increased risk of GERD with an estimated prevalence of 55-90% (27). Like CwCF, regurgitation is a common symptom of GERD in AwCF. On the other hand, heartburn is more commonly reported in adolescents and adults with CF. Abdominal pain or dyspepsia in adults can signify the presence of other gastroduodenal pathology such as gastritis, duodenitis, or peptic ulcer disease, which may warrant further evaluation. Dysphagia could be a sign of esophageal dysmotility or esophageal strictures. Concurrent foregut dysmotility or gastroparesis can manifest with post-prandial early satiety, bloating, nausea, and vomiting and can be difficult to clinically distinguish from GERD. Adults with CF on long-term steroids or immunosuppression following transplant are at increased risk of infectious esophagitis, which may manifest with odynophagia (28).

As with CwCF, GERD in adults with CF is usually a clinical diagnosis if alarm features (ie.dysphagia, anemia, weight loss) are absent, and routine management involves dietary and lifestyle modifications and pharmacological acid suppression with PPIs or H2-RAs. Like CwCF, adults with suspected GERD rarely undergo endoscopy for the diagnosis of GERD. Long-term PPI therapy may not always be necessary in AwCF. Thus, during transitions of care, reassessing the indication for PPI use and considering trials of PPI weaning or discontinuation can minimize unnecessary long-term use.

Routine screening for failure to respond to PPI or for the presence of alarm symptoms should be done at the time of transition. This is especially important considering the substantially increased rate of esophageal adenocarcinoma and Barrett’s esophagus in AwCF compared to the general population with an earlier average age of onset (29). Individuals on long-term PPI with inadequate symptom control, intolerance to medications, alarm features, or complications such as Barrett’s esophagus or esophageal strictures should be carefully considered for upper endoscopy and for surgical management if clinically appropriate. In patients with dyspepsia or suspected peptic ulcer disease who are at high risk for endoscopy, non-invasive testing for Helicobacter pylori such as stool antigen test or breath test may also be considered. Due to frequent symptom overlap and despite lack of clear guidelines for the work-up and management of dyspepsia and dysmotility in AwCF, further endoscopic or motility testing can be considered in those who fail to respond to PPI. Though data is lacking, a systematic review of the literature noted increasing frequency of gastroparesis in CF with increasing age (22). This is thought to be due to the increased risk of diabetes in AwCF. The optimal diagnostic approach for gastroparesis in CF remains an area of debate, however scintigraphy can be considered. If gastroparesis is confirmed, the use of prokinetic agents such as metoclopramide and macrolide antibiotics can be considered as with CwCF. Decompressive gastrostomy tube and gastrojejunostomy feeding tube placement can be considered in cases refractory to medical therapy.

Transition Take-Home Points:

Reassess the indication for PPI and consider discontinuation trial.

Screen for alarm features or poor response to therapy and consider upper endoscopy and surgical referral when clinically appropriate due to a higher risk of Barrett’s esophagus and esophageal cancer.

Transition Take-Home Points:

Identify patients with nutritional deficiencies with symptoms of SIBO and consider for diagnostic evaluation or empiric therapy.

Identify patients with a history of meconium ileus requiring surgical intervention during childhood or PI who are at higher risk of DIOS and constipation.

Obtain a thorough history of previously tolerated and unsuccessful treatments for constipation to guide future care which can include optimizing PERT dosing, adjusting bowel regimens, and consideration of combination therapies.

3. Pancreas

3.3. Pediatrics

Pancreatitis can be one of the initial presentations of CF, especially in milder variants (62). In children with >1 episode of acute idiopathic pancreatitis, genetic testing for mutations including CFTR is recommended. The incidence of acute pancreatitis in pancreatic sufficient (PS) children is 10% in comparison to 0.5% in pancreatic insufficient children (63). Even in those with PS, recurrent acute pancreatitis can progress to PI and CFRD (64). There are case reports of acute pancreatitis in children with homozygous mutations during or after treatment with lumacaftor/ivacaftor (65). Modulator therapy may improve pancreatic acinar mass and function, which is supported by elevated fecal elastase (66, 67). During transitions of care, it is important to communicate duration of modulator therapy, whether the patient is PS or PI, and an assessment of prior episodes of acute pancreatitis.

Adults

As with children, acute pancreatitis is almost exclusively seen in PS with acinar tissue reserve and typically presents in teenage years or adulthood. Among adults with PS, it is estimated that 20% will experience pancreatitis, 18% of which presents as a single episode of acute pancreatitis, 60% with acute recurrent pancreatitis, and 22% progress to chronic pancreatitis (68). Despite the low prevalence of acute pancreatitis in CF, it is important to identify individuals with PS during care transitions in whom a high suspicion for acute pancreatitis should be maintained when presenting with abdominal pain.

Transition Take-Home Points:

Identify PwCF and pancreatic sufficiency by checking fecal elastase.

Acute pancreatitis should be considered as a potential cause of abdominal pain in individuals with pancreatic sufficiency.

Screen for CFRD at time of transition with oral glucose tolerance test, as the risk increases with age due to progressive pancreatic islet cell destruction.

4. Hepatobiliary

4.1. Pediatrics

The prevalence of CFLD is high among CwCF, ranging from 5-68% based on the disease manifestation (72). Focal biliary cirrhosis progressing to multi-lobular cirrhosis is seen in 5-10% of CwCF in the first decade (73). Risks for CFLD is higher in males and those with PI, CFRD, history of meconium ileus, and genetic factors (74, 75). Diagnostic criteria includes 2 of the following: clinical evidence of hepatomegaly or splenomegaly, persistently elevated liver enzymes (>12 months on 3 different occasions), abnormal liver ultrasound findings, and abnormal histopathology (69). Guidelines recommend annual liver enzymes to assess liver function and further investigations for any abnormality. Ultrasound and transient elastography can be a non-invasive modality to assess for fibrosis, but its reliability in identifying early fibrosis, especially in younger children is questionable. Treatment comprises supportive therapy and monitoring/treating complications of cirrhosis and portal hypertension. Surveillance EGD are not routinely done for asymptomatic children even with varices unless they present with bleeding. A study found insufficient efficacy of ursodeoxycholic acid (UDCA) use in CFLD, although it is often clinically used for cholestasis from CFLD (76).

Children with CFLD are at higher risk for malnutrition and nutritional deficiencies. Including dietary medium chain triglycerides and poly-unsaturated fatty acids can provide 130-150% of required daily calories (56). Fat soluble vitamin supplementation and regular monitoring to avoid toxicity is essential in CFLD.

Adults

CFLD is well defined in pediatrics but less clearly described in adults, accounting for 5% of CF mortality (77). However, with the improved life expectancy in CF, CFLD is becoming more prevalent in adults and encompasses a similar spectrum of liver diseases as reviewed in CwCF (70, 77-79). Liver diseases are mainly asymptomatic until they are in advanced stages, therefore early detection is key. Annual screening for CFLD with history, physical examination, laboratory testing, and non-invasive imaging (ultrasound or fibroscan) is recommended (77).

For established CFLD, management involves avoidance of hepatotoxic substances/medications, optimizing nutrition, and managing complications of portal hypertension or liver failure (69). Key management items related to severe liver disease include limiting contact sports (due to splenomegaly), NSAID avoidance in portal hypertension, awareness of cholestatic pruritis, and awareness of sleep and attention disturbances of early hepatic encephalopathy. Liver transplantation is the ultimate treatment for advanced liver disease in CF, however, the timing is a challenge due to progressive pulmonary disease and malnutrition (69). Early referral is recommended to minimize complications.

Transition Take-Home Points:

Identify PwCF with previous liver disease or injury and obtain an initial assessment of their liver function and any signs of chronic liver disease.

Screen for and counsel regarding modifiable risk factors for hepatotoxicity such as alcohol use or recreational drug use.

Esophagus	• Screen for long-term use of PPI, reassess indication, and consider discontinuation trial to reduce unnecessary long-term use. • Screen for alarm symptoms in AwCF with long-standing GERD and consider upper endoscopy when clinically appropriate given the higher risk and earlier onset of Barrett's esophagus and esophageal cancer.
Pancreas	• Identify PwCF with pancreatic sufficiency. ○ Monitor for the development of pancreatic insufficiency from progressive loss of pancreatic function. ○ Consider the possibility of acute pancreatitis in PwCF with pancreatic sufficiency presenting with abdominal pain. ○ Screen for hypertriglyceridemia, tobacco use, and alcohol use that can precipitate further acinar damage and result in pancreatic insufficiency. • Identify PwCF with pancreatic insufficiency. ○ PwCF with pancreatic insufficiency should have fat-soluble vitamin levels checked annually. ○ Assess understanding of the correct use of PERT and optimize dosing. • Monitor for signs of CF-related diabetes from progressive pancreatic islet cell destruction especially in AwCF.
Liver	• Identify PwCF with previous liver disease or injury. • Obtain an initial assessment of liver function and any signs of chronic liver disease. • Screen adolescents and adults for modifiable risk factors for hepatotoxicity such as heavy alcohol use and recreational drug use and provide appropriate counseling.
Nutrition	• Obtain a complete review of previous dietary habits and supplements. • The initial visit should include a comprehensive nutritional assessment and counseling to intervene early if there are any signs of malnutrition. • Assess disordered eating behaviors.
Intestines	• PwCF with nutritional deficiencies or symptoms of SIBO should be identified and considered for diagnostic evaluation or empiric therapy for SIBO • Obtain a thorough diagnostic and treatment history for PwCF previously diagnosed with SIBO to help adult providers plan future care • Identify PwCF with a history of meconium ileus requiring surgical intervention during childhood or pancreatic insufficiency who are at higher risk of DIOS and ensure optimization of PERT and bowel regimen.
GI malignancy	• Individualized GI cancer screening strategies depending on the burden of other comorbidities, transplant status, and severity of pulmonary manifestations should be discussed.

Figure 2. Transition of Care Checklist.

Figure 2. Transition of Care Checklist.

5. Nutritional Failure

Pediatrics 

Underweight and failure to thrive are common manifestations in younger kids with CF (55). Multiple studies have shown a correlation between malnutrition and poor lung function (80). Conversely, with use of highly effective modulator therapy, obesity and disordered eating are on the rise among older kids and adolescents (81).

Due to malabsorption and increased caloric needs, children need ~130-150% of the recommended daily allowance (RDA) for positive energy balance to promote growth. Daily caloric requirements are calculated based on activity levels in older kids. Most of the calories should come from carbohydrates (50%) and the rest from protein (35-40%) and fat (15-20%). Poor absorption is an important cause for malnutrition; hence reviewing the dose of PERT is essential.

Micronutrient deficiencies include fat soluble vitamins, zinc and essential fatty acids should be measured to prevent complications and subsequently monitored to avoid hypervitaminosis (Table 1) (82).

Due to immense focus on nutrition and PERT, obese and overweight individuals have quadrupled in the last decade (83). CFTR modulators are reported to increase weight in CF by improving appetite and reducing malabsorption. These medications also increase HDL, LDL and cholesterol as well as improve insulin secretion (84, 85). It is important to monitor for signs of overnutrition and perform screening labs such as lipid panel annually.

Adults

Malnutrition has previously been one of the most common manifestations of AwCF, and survival is linked to nutritional status (86). Corey et al compared the median survival for two large CF clinics with different dietary approaches. Patients with a high-calorie, high fat diet had better nutritional status and improved median survival. This led to the recommendation of high-calorie, high fat and dietary supplements to help maintain nutritional status in CF (87). However, most of the clinical studies were focused on children. There has been limited data on nutrition in AwCF. A retrospective analysis of 81 AwCF revealed that malnutrition is still a prevalent issue a more aggressive nutritional approach is required (88). Given the improved survival with better nutrition and highly effective modulator therapy, a complete review of current and previous dietary habits and supplements is warranted. The initial transition visit should include a comprehensive nutritional assessment and counseling to intervene early if there are any signs of malnutrition. Supplemental enteral feeding when non-invasive approaches fail to improve nutritional status may be required. Some studies looked at the benefits of enteral feeding in CF and these studies showed evidence of weight gain, improved body composition and improved pulmonary function in one of the studies(89-91).

On the other hand, high-calorie and high-fat diet may increase risks of obesity, cardiovascular complications, CFRD, and fatty liver disease. Data is limited on the detriments of obesity in PwCF. A study showed better pulmonary function in obese or overweight PwCF when compared to normal or underweight individuals and suggested a cutoff BMI <30 kg/m2 (92). Providers should assess for obesity at the time of transition to minimize future complications.

Transition Take-Home Points:

Obtain a complete review of previous dietary habits and supplements.

Evaluate for signs of malnutrition, obesity/overweight and disordered eating during the initial transition visit.

6. GI Cancers

Transition Take-Home Points: 

Carefully investigate for any alarm or unexplained GI symptoms during transition of care. Individualized GI cancer screening strategies depending on the burden of other comorbidities, transplant status, and severity of pulmonary manifestations should be discussed during care transitions.

7. Conclusion

Abbreviations

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