Expert Review of Gastroenterology & Hepatology

ISSN: 1747-4124 (Print) 1747-4132 (Online) Journal homepage: https://www.tandfonline.com/loi/ierh20

Gastrointestinal pathophysiology and nutrition in

cystic fibrosis

Thomas L. Ratchford, Jeffrey H. Teckman & Dhiren R. Patel

To cite this article: Thomas L. Ratchford, Jeffrey H. Teckman & Dhiren R. Patel (2018)
Gastrointestinal pathophysiology and nutrition in cystic fibrosis, Expert Review of Gastroenterology
& Hepatology, 12:9, 853-862, DOI: 10.1080/17474124.2018.1502663

To link to this article: https://doi.org/10.1080/17474124.2018.1502663

Accepted author version posted online: 18

Jul 2018.
Published online: 03 Aug 2018.

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EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY
2018, VOL. 12, NO. 9, 853–862
https://doi.org/10.1080/17474124.2018.1502663

REVIEW

Gastrointestinal pathophysiology and nutrition in cystic fibrosis

Thomas L. Ratchford, Jeffrey H. Teckman and Dhiren R. Patel
Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Saint Louis University School of Medicine, Saint Louis, Missouri, USA

ABSTRACT ARTICLE HISTORY

Introduction: Cystic fibrosis (CF) is a severe, progressive, multisystemic disease that is caused by Received 16 May 2018
mutations in the cystic fibrosis transmembrane conductance regulator gene. Optimizing nutrition is Accepted 17 July 2018
critical, as higher growth parameters are associated with better pulmonary function and outcomes, but KEYWORDS
unfortunately patients with this disease are prone to malnutrition, growth failure, and vitamin defi- Cystic fibrosis
ciencies. The purpose of this review is to provide a timely highlight of the physiologic processes and transmembrane
outcome data to support today’s management strategies, as well as review these principles themselves. conductance regulator
Areas covered: This review covers the background of the importance of vigilant attention to nutrition (CFTR); cystic fibrosis; enteral
and growth in these patients, the underlying physiology leading to an abnormal gastrointestinal tract nutrition; failure to thrive;
and its role in CF malnutrition, and current evaluation and management strategies to address nutrition growth failure;
malabsorption; nutrition;
in CF. Analysis of up-to-date relevant literature was performed using PubMed. Pancreatic enzyme
Expert commentary: Advances in research and clinical developments over the years have improved replacement therapy (PERT);
knowledge of this disease as well as patient outcomes. Of particular importance is optimizing nutrition pancreatic insufficiency;
especially in the early stages of life, as well as accounting for the markedly abnormal CF intestinal milieu vitamin deficiency
when addressing the gastrointestinal and nutritional needs of these patients.

1. Introduction objective anthropometric parameters. Infants diagnosed with CF

via newborn screening, and thus introduced to nutritional thera-
Cystic fibrosis (CF) is a progressive, autosomal recessive genetic
pies at an earlier age, have greater growth than those diagnosed
disorder that causes shortened life spans [1,2]. Though mainly
later in infancy and childhood [7]. However, special caution must
diagnosed in Caucasians, it is also seen in patients of other ethnic
be used, as new data suggests that even when promptly diag-
and racial backgrounds, and in the United States the mean
nosed with CF by newborn screening and introduced to appro-
prevalence is 0.74 in 10,000 persons. It is caused by mutations
priate nutritional therapies, infants with CF-related pancreatic
in the cystic fibrosis transmembrane conductance regulator
insufficiency (PI) will have notable rates of undernutrition and
(CFTR) gene, which encodes the CFTR protein. The lack of ade-
stunting by 2 years of age, and so these children may need even
quately functioning CFTR protein causes disruption of transport
more attention in early life than currently given [8]. This is espe-
of sodium and chloride ions across cell membranes, leading to
cially important given recent findings demonstrating that infants
thickened mucus secretions in organs throughout the body
with CF and PI who recovered birth weight z-scores by 2 years of
including the lungs, pancreas, liver, gallbladder, and intestines
age were more likely to maintain better anthropometrics through
[1,3]. The combination of impaired intestinal absorption and
12 years of age, while infants who did not achieve growth targets
increased metabolic demand to achieve homeostasis leads to
were more likely to continue suboptimal growth later in child-
challenges in providing adequate nutritional intake, and these
hood; in fact, in that study cohort, none of the studied patients in
patients are prone to malnutrition and vitamin deficiencies [4]. In
this latter category were able to achieve additional consistent
recent years, the major focus to limit morbidity and mortality in
catch-up growth between 2 and 12 years of age [9]. A possibly
CF has been its pulmonary manifestations. However, optimizing
more important reason for achieving early growth targets is that
growth and nutrition is paramount in patients with CF, especially
young children with CF and PI who regained their birth weight-
children, as the medical literature is clear that undernourished CF
for-age z-score within 2 years of their CF diagnosis had better
patients, whether children or adults, are more likely to experi-
pulmonary function at age 6 than those who did not regain their
ence poorer clinical outcomes, including reduced lung function
birth weight z-score within 2 years [10]. Konstan et al. demon-
[3–6]. This article will review the significance, pathogenesis, eva-
strated that children with CF whose weight-for-age measurement
luation, and management of the nutritional aspects of CF.
at age 3 years was below the 5th percentile had significantly
decreased lung function at age 6 years compared to children
2. Background: growth and outcomes in CF with CF whose weight-for-age measurement was over the 75th
percentile at age 3 years [11]. In an observational, prospective
Several studies have associated improved outcomes in pediatric
study of over 3000 CF patients enrolled in the Cystic Fibrosis
and adult CF patients at multiple stages of life having higher

CONTACT Dhiren R. Patel [email protected] Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Saint Louis
University School of Medicine, 1465 S Grand Blvd, St. Louis, MO 63104
© 2018 Informa UK Limited, trading as Taylor & Francis Group
854 T. L. RATCHFORD ET AL.

Foundation (CFF) Registry, higher weight-for-age percentile at age cause disease. Specific mutations cause dysfunction in the
4 years was associated with higher rates of survival, fewer compli- CFTR protein in different ways, and six different classes have
cations, improved pulmonary function, higher body mass index been defined to categorize the nature of the protein’s dys-
(BMI), and greater height at 18 years of age [12]. Data from the CFF function. The cause of dysfunction has been identified as
Registry from 1994 to 2003 showed that in patients with CF and PI, defective protein production, defective processing, defective
higher BMI was correlated with higher objective pulmonary func- regulation, defective conduction, reduced amounts of func-
tion in children aged 6–12 years and 13–20 years, as well as adults tional protein, and enhanced turnover of protein, in classes I,
aged 21–40 years [13]. Studies have shown that in addition to II, III, IV, V, and VI, respectively. Classes I, II, and III have more
achievement of growth, maintenance of growth is also important, severe disease phenotypes and are more strongly associated
as a more severe rate of decline in BMI in adolescence in CF with PI. Of note, the F508del mutant is included as a class II
patients was significantly associated with a substantial decline in mutation and correlates with the high prevalence of PI in CF
lung function in young adulthood [14]. Furthermore, in subgroups patients in the United States [19–21].
of both school-aged children and adolescents of a large German The CFTR protein, a cyclic adenosine monophosphate-regu-
cohort with data obtained over 1996–1997, improvement in lung lated chloride channel, is located on the apical surface of
function was correlated with gains in weight-for-height measure- epithelial cells in many organs of the body and regulates the
ments, and worsening lung function was correlated with loss or secretion and absorption of several other ions in addition to
stasis in weight-for-height measurements [15]. Because of the vast chloride, including sodium, bicarbonate, and potassium [20].
body of data correlating weight gain with improved outcomes in When this channel is dysfunctional as seen in CF, secretions
CF, much attention should be directed toward optimizing growth from the affected organs are abnormal [3]. Loss of excess
and nutrition in these patients. Malnutrition must be not only sodium and chloride in the skin leads to increased need for
aggressively treated, but also closely monitored for and avoided. replenishment [1,6]. Mucus secreted in the lung, pancreas,
Bringing some caution to this historical approach, there has hepatobiliary system, and gastrointestinal (GI) tract is much
been some recent longitudinal data showing an increase in thicker than normal, as water, which follows the chloride ions
overweight adult patients with CF over the past few decades into the lumen, does not flow as usual [19,20]. This abnormal
[16]. Furthermore, an adult study showed that improved lung mucus has drastic, wide-ranging consequences, as the thick-
function in CF patients was associated with fat-free body mass, ened secretions and released enzymes cause significant
rather than BMI, and that in fact, fat mass index and percent damage to secretory ducts and organs [22,23]. In the lungs,
body fat were inversely associated with improved lung func- the abnormally thick and adherent mucus is difficult for cilia to
tion [17]. In the pediatric literature, a single-center study clear, colonization of pathogenic bacteria occurs as a result, and
demonstrated that no improvement in lung function was neutrophil-released elastase cause damage to lung parench-
seen in CF patients who were overweight or obese compared yma [19,23]. These insults lead to a pro-inflammatory milieu, an
to CF patients with normal weight or who were at risk of increased frequency and severity of pulmonary infections, and,
nutritional failure (though as one would expect, the poorest over time, bronchiectasis and decreased lung function [23]. The
lung function was seen in patients in nutritional failure) [18]. pancreas is also severely affected, as thickened secretions cause
Thus, data regarding overweight and obese CF patients is obstructions in the pancreatic ducts and thus impair the trans-
relatively new and developing but seems to suggest that port of digestive enzymes and pancreatic bicarbonate to the
increased lean body mass rather than BMI is key to improved intestinal lumen, leading to exocrine PI, poor absorption of fat
outcomes. However, given the well-established data showing soluble vitamins (A, D, E, and K), and an acidified intestinal tract
poor outcomes in undernourished CF patients, as well as the [2,4,21]. It should be mentioned, however, that while cystic
needs of the growing children, the authors advocate for the fibrosis-related diabetes (CFRD) is traditionally thought to
utilization of current, published anthropometric targets by develop from pancreatic islet β-cell destruction by mucus,
both CFF and the European Society for Clinical Nutrition and newer evidence suggests that this mechanism is more complex.
Metabolism (ESPEN), until more robust pediatric data emerges. In addition to this, CFRD has a component of insulin resistance
in addition to insulin deficiency, the mechanism of which
remains unclear [24]. The intestines of CF patients are further
altered by the abnormal functioning of Brunner’s glands, where
3. Pathogenesis of malnutrition in CF
CFTR is highly expressed [2,25]. Acidification of the intestinal
The pathogenesis of malnutrition in CF is multifactorial. The lumen impairs pancreatic enzyme function, whether the
major components of this process, which are increased meta- enzymes are endogenous or provided as exogenous supple-
bolic demands to maintain respiratory function, abnormal ments, and also likely impairs micelle formation and other
electrolyte losses, and malabsorption, are complications aris- luminal biochemical events critical to absorption [25,26].
ing from the defective CFTR membrane protein. Dysfunction Furthermore, micelle formation and absorption is certainly dis-
of the CFTR membrane protein is caused by mutations in the rupted from the abnormal bile circulation found in CF patients,
CFTR gene, located at 7q31.2. Currently, over 1,900 CFTR muta- as they have decreased absorption of bile acids in the terminal
tions have been identified, the most common being a deletion ileum, leading to increased losses of bile in the stool [27]. In an
at position 508, annotated as F508del [19]. In the United attempt to neutralize the acidified digestive tract to a more
States, this mutation is homozygous in 48% of patients, and physiologic state, multiple studies have been performed mea-
heterozygous in 40% [20]. Any of the hundreds of other suring the clinical benefits of acid suppression in CF patients,
mutant CFTR alleles can pair with each other or F508del to but results have been mixed with no definite conclusions made
 EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 855

Figure 1. Factors contributing to the abnormal intestinal milieu of patients with cystic fibrosis.

regarding efficacy, and so trialing proton pump inhibitors in human studies, based on the authors’ clinical experience,
individual patients may be considered, with caution, especially this management principle is translatable to clinical medicine,
in patients prone to small bowel bacterial overgrowth and some symptoms (e.g. abdominal pain, bloating) theoreti-
(SBBO) [26]. cally derived from thick mucus in the small bowel may be
The accumulation of abnormally thick mucus in the intes- relieved with a daily dose of a polyethylene glycol-based stool
tines is widely thought to play a major role in the anomalous softener. Also, on occasion, a limited, empiric course of oral
intestinal milieu, though the exact mechanisms in digestion metronidazole for presumed SBBO when suggestive symp-
and intestinal transit time has not yet been well-defined toms are present may be helpful.
[2,25,26]. One set of views proposes that thickened CF intestinal To summarize the many abnormalities detailed in this section,
mucus overlies the epithelium and leads to an abnormal Figure 1 shows the components contributing to the aberrant
chyme–epithelium interface, causing decreased absorption of intestinal environment of patients with CF. All of these factors
nutrients [2,28,29]. Another hypothesis proposes that the together lead to the marked malabsorption of nutrients and bile
abnormally thick intestinal mucus causes stasis of intestinal acids, the latter of which further contributes to poor absorption
contents and serves as a biofilm, the combination of which of the fats and fat-soluble vitamins [25]. On top of this, patients
leads to dysbiosis and frequent SBBO [25,28,30]. Going further, with CF-related liver disease (CFLD) are also at a higher risk of fat-
some hypothesize that the intestinal smooth muscle itself soluble vitamin deficiency due to cholestasis [4,5,20]. Thus, the
develops dysmotility, based on experiments in CF-mutant combination of increased metabolic demands to maintain
mouse models. While the mechanism is not fully understood, respiratory function, abnormal electrolyte losses throughout
it is not believed to be a direct effect of CFTR, but more likely the body, and malabsorption form the backbone of malnutrition
related to a complex network involving differing expression in in CF patients.
prostaglandins, possibly influenced by dysbiosis as mentioned
above [31–33]. In humans, these mechanistic studies have not
taken place, but at least one study used a magnet-based moti- 4. Nutritional evaluation
lity tracking system to demonstrate delayed passage of the
magnet through the small intestine to the cecum in CF patients, 4.1. Estimated energy requirements
with a trend (although not statistically significant) of decelera- Due to the pathogenesis of disease as described above, children
tion as the magnet moved distally, rather than a consistent slow and adults with CF require extra caloric intake compared to their
rate. These findings would mirror clinical experiences in CF non-affected counterparts. Historically, the standard of care in
patients, with meconium ileus and obstruction typically devel- regards to nutrition in CF has been a high-fat, high-calorie diet
oping in the distal, rather than proximal, small intestine [34]. with pancreatic enzyme replacement therapy (PERT) and supple-
In terms of practical management of subsequent abdom- mentation of fat-soluble vitamins [3]. Though individual energy
inal symptoms such as bloating, constipation, and abdominal needs can vary based on multiple factors (e.g. frequency of
pain, De Lisle et al. showed that CF-mutant mice hydrated pulmonary exacerbations, degree of malabsorption, presence/
with polyethylene glycol-based laxative rather than water had absence of CFLD, and/or CFRD, individual compliance with thera-
a significant reduction in intestinal mucus accumulation and pies), guidelines from both Europe and the United States advise
bacterial load compared to the CF-mutant mice hydrated only higher caloric intake in patients with CF [3]. European guidelines
with water, and also produced some evidence that this treat- recommend energy intake for CF patients be 120–150% of the
ment also improved intestinal smooth muscle activity in that daily caloric load taken by unaffected individuals, and the CFF
model [30,33]. While not carefully evaluated in controlled recommends intakes of 110–200% of that of the standards for
856 T. L. RATCHFORD ET AL.

unaffected individuals [13,35]. It is important to remember that bilirubin, blood cell counts, iron status, plasma fat-soluble vitamin
the supranormal intake required for positive energy balance in levels, plasma, or serum phospholipid fatty acid patterns, and, to
CF is likely to overwhelm the intestinal absorptive capacity, given evaluate for exocrine pancreatic function in patients who have not
the current level of therapeutic technologies. Therefore, inter- yet been diagnosed with PI, an annual fecal pancreatic elastase-1
mittent steatorrhea is common and expected – even in patients measurement [3]. Obtaining annual coagulation factors, including
taking enzyme supplements and other treatments appropriately. prothrombin time, to assess for coagulopathy due to vitamin K
In this situation, increasing doses of exogenous enzymes beyond deficiency is also advisable. If initially normal, the fecal pancreatic
the recommended ranges will not reduce steatorrhea or improve elastase-1 measurement may need to be repeated more fre-
absorption. quently during the first year of life, as PI frequently develops in
infancy, and PERT should be initiated when this laboratory mea-
surement is abnormally low, even in the absence of symptoms
4.2. Growth parameters [36]. As decreases in BMI have been observed to occur years
before CFRD diagnosis, all CF patients should be screened for
Because of the outcomes evaluated in the studies mentioned in
glucose tolerance annually beginning at 10 years of age with an
the Background section, as well as overall feasibility, different
oral glucose tolerance test [3,24]. Starting at 8–10 years of age,
anthropometric benchmark measures should be utilized based
dual-energy X-ray absorptiometry is recommended every
on age to assess nutritional status in CF patients. In CF patients
1–5 years (specific interval depends on multiple factors) to assess
with adequate nutritional status, routine nutritional assessment
bone health. Lastly, a dietary review, including questions related to
including weight and length measurement (as well as head
recommended dietary plans, is recommended every 3 months in
circumference measurements in children below 24 months of
children, as well as every 6 months in adults [3].
age) should occur every 3 months. However, closer attention to
growth and nutritional status is essential in the first year of life,
during the first year of diagnosis, during the peripubertal per- 5. Evaluation and management of poor growth and
iod, and whenever nutritional status is judged to be suboptimal malnutrition in CF
[5,6]. For this reason, ESPEN recommends evaluation and mea-
surements every 1–2 weeks then monthly for the first year of 5.1. Initial management
life, until clear establishment of adequate nutrition, after which Because of the association of poorer overall outcomes with
visits can be spaced to every 3 months [3]. malnutrition in CF, both patient-specific and CF-related factors
For children under 2 years of age, weight, height, and of poor growth and nutritional deficiencies should be investi-
weight-for-length percentiles should be utilized in nutritional gated without delay in patients with at-risk or failing nutri-
assessment. CF patients in this age group should achieve a tional status [3,5,6]. Initially, immediately identifiable issues
weight-for-length percentile greater than or equal to the 50th should be recognized and promptly corrected. These factors
percentile on Centers for Disease Control and Prevention (CDC) include inadequate diet by patient/parent history, clinically
growth charts. CDC growth charts are preferred to World Health obvious malabsorption (frequent steatorrhea or poor adher-
Organization (WHO) growth charts, as WHO charts assign a ence to (PERT), and recurrent pulmonary exacerbation [6].
higher percentile for the same weight, and CF patients at the Thorough multidisciplinary assessment is warranted if an
50th percentile for weight-for-length by WHO definition were immediately obvious cause of poor growth is not identified, if
found to have lower forced expiratory volumes than those at suboptimal growth continues over multiple time points, or if
the 50th percentile by CDC definition [6]. For children the degree of malnutrition is severe. Interventions to correct
2–18 years of age, maintaining a BMI percentile equal to or the patient’s nutritional status should occur in concert as the
greater than the 50th percentile for age should be the desired nature of the patient’s malnutrition is investigated [5,6].
target. For adults over the age of 18 years, CF patients should
have a BMI equal to or greater than 22 kg/m2 and 23 kg/m2, for
females and males, respectively [3,6]. Patients not meeting 5.2. Diagnostic considerations
these criteria, and those who fail to gain weight between visits,
The differential diagnosis of poor growth is broad, as it
should be identified as having an at-risk nutritional status, and
includes etiologies of failure to thrive generalizable to all
evaluation and management of their poor growth should
children, as well as those specific to CF and the individual
begin. If at any time the weight-for-length or BMI (depending
patient. As malnutrition in CF patients is often multifactorial
on the age of the patient) crosses below the 10th percentile for
with one or several comorbid diagnoses contributing to the
age, or if their growth curve inappropriately flattens or declines
poor nutritional status, evaluation by a multidisciplinary team
over multiple visits, they should be more aggressively evalu-
is needed. This group should include a pulmonologist, gastro-
ated and managed for failure to thrive [3].
enterologist, endocrinologist, dietician, social worker, psychol-
ogist, clinical nurse, and the patient’s primary care provider
[6,37]. The differential diagnosis may be age-specific, and
4.3. Other measures
there are multiple subspecialty considerations, with some
In addition to growth parameters, periodic monitoring of bio- diagnoses having more clinical impact than others. Potential
chemical nutritional markers, bone mineral density, and dietary etiologies are gastrointestinal (PI, celiac disease, gastroesopha-
history should occur. ESPEN recommends consideration of yearly geal reflux disease, constipation, dysmotility, inflammatory
analysis of blood electrolytes, serum transaminases, albumin, bowel disease, CF-associated liver disease, SBBO, insufficient
 EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 857

Table 1. Common gastrointestinal symptoms and actions to consider in cystic fibrosis patients.
Symptom Potential etiology Actions to consider
Abdominal Accumulation of thick mucus in intestinal Daily polyethylene glycol-based laxative
pain lumena
SBBOa Course of antibiotics (metronidazole, rifaximin, etc.)
Pancreatitis (acute, acute recurrent, or Hospital admission, abdominal ultrasound, pain control, further evaluation by gastroenterologist
chronic)a
GERDa Course of proton pump inhibitor
Constipationa Polyethylene glycol-based laxative
Malabsorption/PIa Optimization of PERT (dosage and delivery)
Inflammatory Bowel Disease Further evaluation by gastroenterologist
Helicobacter pylori infection Further evaluation by gastroenterologist
Functional abdominal pain Further evaluation by gastroenterologist
Gallbladder disease Abdominal ultrasound
Eosinophilic esophagitis/gastroenteritis Further evaluation by gastroenterologist
Celiac disease Obtain serum anti-tissue transglutaminase IgA antibody
Diarrhea Malabsorption/PIa Optimization of PERT (dosage and delivery)
SBBOa Course of antibiotics (metronidazole, rifaximin, etc.)
High enteral intakea Continued clinical surveillance
Celiac disease Obtain serum anti-tissue transglutaminase IgA antibody
Inflammatory bowel disease Further evaluation by gastroenterologist
Infectious Enteritis (bacterial or parasitic) Stool cultures, stool testing for Clostridium difficile, stool ova and parasite examination
Poor weight Inadequate caloric intakea Review of diet, dietician consultation, nutritional optimization, consideration of supplemental/
gain enteral nutrition
Malabsorption/PIa Optimization of PERT (dosage and delivery)
Pulmonary Exacerbationa Further evaluation by pulmonologist
SBBOa Course of antibiotics (metronidazole, rifaximin, etc.)
CFLDa Further evaluation by hepatologist
CFRD/insulin resistancea Glucose tolerance test, further evaluation by endocrinologist
GERDa Course of proton pump inhibitor
Dysmotilitya Further evaluation by gastroenterologist
Inflammatory Bowel Disease Further evaluation by gastroenterologist
Celiac disease Obtain serum anti-tissue transglutaminase IgA antibody
Eosinophilic esophagitis/gastroenteritis Further evaluation by gastroenterologist
Food insecurity Further evaluation by social worker
Depression Further evaluation by psychologist and/or psychiatrist
Eating disorder Further evaluation by psychologist, psychiatrist, and adolescent medicine specialist
Issues with patient compliance Discussion with family, further evaluation by social worker and/or psychologist
a
Denotes issues and conditions particularly specific to patients with cystic fibrosis.

caloric intake, eosinophilic gastrointestinal disease, enteral under the age of 2 years, PERT should be initiated in those who
infectious disease), pulmonary (CF pulmonary exacerbation), have two CFTR mutations known to cause PI, in those whose fecal
endocrine (CFRD), psychological/psychiatric (mood disorders, pancreatic elastase-1 is less than 200 µg/g in a formed stool, in
body image disorders, eating disorders), socioeconomic (food those under 6 months of age whose fecal coefficient of fat absorp-
insecurity, economic stressors), and patient-specific (lack of tion is less than 85%, and in those who have clear signs and
compliance to medications, PERT, and/or dietary recommen- symptoms of PI (while awaiting results of confirmatory testing)
dations) (see Table 1) [1,4–6,20,25,37]. [36]. Multiple PERT dosing guidelines have been published for
As these etiologies are being investigated, initial actions to infant, children, and adults [1,3,13,35,36]. Despite this, Calvo-
manage the suboptimal or poor weight gain should begin [6]. Lerma et al. demonstrated much variability of PERT dosing
Nutritional interventions in the nutritionally-failing patient between patients and centers, as PERT efficacy is affected by
focus on three main tenets: correcting any identified medical multiple factors, including disease state, diet composition, and
co-diagnoses as mentioned above, optimizing PERT, and patient compliance [1,39]. Proper administration of PERT is impor-
increasing caloric intake [3,5,6,36]. tant to prevent inactivation of the enzymes before delivery to the
duodenum, so proper teaching of PERT administration should
occur with the patient and caretakers [40]. Overall response to
5.3. Pancreatic enzyme replacement therapy PERT should be assessed regularly, and signs of malabsorption
(e.g. steatorrhea, abdominal bloating) or poor weight gain despite
PERT involves the delivery of multiple exogenous (porcine), enteri- appropriate caloric intake should cause the clinician to consider
cally-coated, pancreatic enzymes, especially lipase, amylase, and increasing the dose, but not above the recommended ranges, as
protease, to the lumen of the duodenum in order to facilitate excessive dosing of PERT above the daily maximum value
digestion of fat and protein [1,3,21]. This therapy is indicated for increases the risk of fibrosing colonopathy [1,4,35].
exocrine PI, which usually presents during early infancy but may
develop later in life [21,36]. Currently, there are multiple methods
to evaluate for PI, including measurements of pancreatic fluid in
5.4. Dietary and behavioral evaluations
the duodenum as well as 72-hour fecal fat collection, but given its
accuracy and convenience, fecal pancreatic elastase-1 is most Optimizing caloric intake is critical in the poorly growing CF
practical, particularly as a screening test [21,38]. In CF patients patient, and this entails the enhancement of both feeding
858 T. L. RATCHFORD ET AL.

behaviors and feeding content. Baseline intake should be well- aforementioned, less invasive techniques, as the percutaneous
determined. A 24-hour dietary recall is a practical, in-office first route often allows more rapid resumption of pulmonary toilet
step in this endeavor, though a prospective, 3–5 day dietary and other activities [41]. Nasogastric tubes are recommended
log is advised for a more accurate assessment of intake [3,5]. If when supplemental tube feeds are anticipated to last
caloric intake is low, behavioral evaluation toward food intake 3 months or less [41]. If a comorbidity, such as pancreatitis,
should occur [5]. Targeted behavioral therapy can be helpful severe gastroesophageal reflux or gastroparesis, prevents tol-
in young children, and is recommended in young children erance of gastric feeding, gastrojejunal or jejunal tube feeds
who are not meeting caloric needs or have identified beha- may be employed [6,41]. While supplemental enteral nutrition
vioral challenges at mealtime [37]. In adolescents and adults, can be given in boluses or at a longer, continuous rate, the
concerns about body image should be addressed if negatively CFF recommends supplementation in the form of continuous
impacting food intake [6]. nocturnal infusions, as this may prevent decreases in oral
nutritional consumption while the patient is awake during
the daytime [5,41]. There is no consensus for CF patients
5.5. Oral nutritional supplementation
over 2 years of age regarding the type of enteral formula
In addition to addressing feeding behaviors, nutritional con- given (polymeric, semi-elemental, or elemental), and patient-
tent should be appropriately adjusted. In infants, human specific factors should be considered by the multidisciplinary
breast milk is the initial form of nutrition recommended by care team [3,6,36,41]. The authors’ personal experience is that
the CFF, but standard (nonhydrolyzed) infant formulas are also formulas closer to isotonic osmolality are better tolerated than
appropriate and are recommended by the CFF if human breast concentrated, hypertonic alternatives, even if a larger volume
milk is not utilized [36]. In the setting of suboptimal weight of the isotonic formula is needed to provide the same caloric
gain in infancy, trialing a hydrolyzed or elemental formula can load, as it seems to the authors that hypertonic feeds tend to
be considered, especially if a diagnosis of milk protein intoler- exacerbate symptoms of bloating, abdominal pain, and diar-
ance or another allergic disorder is suspected, though there is rhea. The authors hypothesize that this observation may be
no recommendation for the routine use of specialized formu- explained by the previously described CF intestinal environ-
las in infants with CF [3,36]. Caloric concentration of the ment that already contains abnormally thickened, concen-
infant’s feed, whether human milk or formula, should be trated mucus.
increased in the setting of suboptimal weight gain, in addition
to the initiation or increasing of PERT as mentioned previously
5.7. Parenteral nutrition
[36]. In older children and adults, dietary interventions start
with the maximization of high-calorie, high-fat foods in the Parenteral nutrition is not typically advised as a nutritional
patient’s diet, and the initiation of oral nutritional supple- support for patients with CF because of its substantial burden
ments in addition to (rather than replacing) these foods [4– (i.e. need for central access, cost, and maintenance), risk of
6]. Medications to stimulate appetite, including cyprohepta- infection, and risk of parenteral nutrition-associated liver dis-
dine, megestrol acetate, and dronabinol, may be considered in ease. Recommended use is limited to exceptional instances
this setting, with the risks of the potential medication side when enteral feeding is not possible, such as in the post-
effects taken into account for each patient [1,4,6]. While these operative period of a major gastrointestinal surgery, in an
medications are commonly used, in the authors’ experience infant with meconium ileus, or in intestinal failure or short
they are seldom able to restore normal growth when used bowel syndrome [3,6].
alone in undernourished patients.
5.8. Vitamins, minerals, and micronutrients
5.6. Enteral nutritional supplementation
CF patients are at increased risk for micronutrient deficiency,
Despite best efforts by patients and providers, maintenance of and they require monitoring and supplementation of multiple
adequate growth via the oral route is often unable to be vitamins and minerals [5]. Although fat malabsorption in
achieved, and initiation of supplemental enteral feeding is patients with PI and cholestasis in patients with CFLD puts
required. The CFF advises starting enteral tube feeds when them at high risk of fat-soluble vitamin deficiency, all CF
oral caloric intake is insufficient in meeting anthropometric patients are at risk of this complication, and obtaining serum
benchmarks despite treatment by a multidisciplinary team levels of vitamins A, D, E, and K is recommended at diagnosis
[6,41]. Because of the frequency of this necessity, as well as as well as annually [3,5]. Though less sensitive, prothrombin
its beneficial effects, information regarding enteral tube feeds time is commonly obtained as a surrogate marker for vitamin
should be presented to the patient and family early in life, and K [1,3]. Additionally, in patients with PI, ESPEN recommends
it should be introduced as a positive tool utilized to bring checking fat-soluble vitamin levels 3–6 months after initiation
about better outcomes [5,6]. The gastrostomy tube, whether of vitamin and enzyme supplementation or a change in vita-
placed via laparoscopic surgical technique, percutaneous min dosing [3]. Multiple formulations of fat-soluble vitamins
endoscopic technique, or radiologic technique, is the most tailored to CF patients are commercially available, and these
commonly utilized enteral feeding medium used for long- supplements should be given with PERT and fat-containing
term enteral feeding [6,41]. The CFF recommends against the food to maximize absorption [1]. Dosing of these vitamins is
open surgical technique for gastrostomy tube placement in CF guided by obtained serum levels, and CF patients often
patients unless there is a clear contraindication against the require doses above the upper recommended dietary
 EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 859

reference intake for unaffected individuals [1]. However, when 6. Nutritional effects of novel therapies in CF
deficiencies are detected, lack of absorption and lack of
Much research is directed toward novel therapies for CF, and
patient adherence should be ruled out before increasing the
some developments, though not their primary purpose, have an
dosage [3]. Deficiencies in water-soluble vitamins are usually
impact on nutrition and growth in this disease [44,45].
uncommon except in atypical circumstances, such as vitamin
CFTR modulators, drugs that modify the function of the defec-
B12 deficiency following a large ileal resection for meconium
tive CFTR protein in CF, are major recent advances in CF [44,46].
ileus [3].
The first CFTR modulator, ivacaftor, was approved by the U.S. Food
In addition to vitamin deficiencies, CF patients are at risk for and Drug Administration (FDA) in 2012 [46]. Over a 48-week
insufficient amounts of minerals due to losses from sweat, period, this drug, compared to placebo, improved z-scores for
malabsorption, and chronic inflammation [3]. Sodium defi- weight and BMI in CF patients over 6 years of age having at
ciency is of particular concern, especially during infancy (par- least one G551D-CFTR mutation [6,47]. In a small sample of chil-
tially due to relatively low sodium content in breast milk and dren from 12 to <24 months of age with a specific CFTR mutation,
infant formulas) and during times of excessive fluid loss such patients on ivacaftor maintained growth velocity and had
as when exercising or experiencing vomiting or diarrhea from increased fecal elastase measurements over a 24-week period
an illness. Because of this, the CFF recommends providing [48]. A second CFTR modulator, lumacaftor/ivacaftor, was
infants with CF 1/8 teaspoon of table salt per day from diag- approved by the FDA in 2015 for patients 12 years of age and
nosis until 6 months of age, and then 1/4 teaspoon of table over who have a homozygous F508del mutation [46]. This newer
salt per day from 6 months of age until 2 years of age, not to drug, compared to placebo, was shown to improve BMI in patients
exceed 4 mEq/kg/day [36]. In older patients eating a Western with this mutation and demographic in randomized controlled
diet with traditionally high sodium content, additional sodium trials over 24 and 96 weeks [49,50]. Lumacaftor/ivacaftor was later
supplementation is usually only needed in times of excessive shown to improve BMI z-score over 24 weeks in patients from 6 to
losses, such as in hot weather, when exercising, or when 11 years of age with the homozygous F508del mutation [51]. It is
experiencing symptoms of illness (fever, vomiting, and diar- important to note that despite these promising findings, the long-
rhea). In these times, small amounts of salt can be added to term effects, if any, of these medications on both pancreatic
sports drinks, or salt tablets can be consumed [1]. Iron defi- function and growth in CF patients are not known at the present
ciency is frequent in CF patients and should be screened for time, especially as the exact mechanism by which these drugs
annually with serum iron levels, and if low, iron deficiency have led to these relatively short-term gains – whether it be via
anemia must be differentiated from anemia of chronic disease reducing the number of pulmonary exacerbations, improving
before providing iron supplementation, per ESPEN guidelines exocrine pancreatic function, normalizing the intestinal milieu, or
[3]. Though CF-specific multivitamins are known to contain by other means – is undetermined for the time being [52].
zinc, additional supplementation may be needed for patients Currently, it is estimated that CFTR modulators are available for
in whom zinc deficiency is suspected, particularly in breastfed approximately half of CF patients in the United States [44,46].
infants who are not fed meat by 6 months of age and develop Multiple other promising drugs targeting the CFTR protein are
poor growth, or in patients with inexplicable growth arrest, currently in various phases of clinical trials, and with wider use,
severe malabsorption, eye problems, increased susceptibility growth and nutrition in the CF population may improve [6,44].
to infections, or prolonged diarrhea [1,3]. The CFF recom- Due to the malnutrition and growth failure often seen in CF,
mends empiric zinc supplementation for up to 6 months in recombinant human growth hormone (GH) has attracted clinical
CF patients with failure to thrive if caloric intake and PERT are interest as a potential therapy. A 2015 Cochrane Review examined
otherwise appropriate [5,36]. Because of its importance in four studies involving recombinant GH therapy in CF patients and
bone health, both the CFF and ESPEN recommend calcium found improvements in some anthropometric parameters when
intake and levels be, at a minimum, kept at the recommended compared to no treatment. However, the authors concluded that
amounts for the unaffected, healthy populations of the same long-term, randomized clinical trials in patients with CF were
age [3,5]. ESPEN does not recommend routine supplementa- needed before a recommendation could be made for routine
tion of selenium in CF patients [3]. Deficiencies of essential utilization [53].
fatty acids (EFA), including linoleic and alpha-linolenic acids, Relizorb™, a single-use, in-line cartridge designed to improve
can occur in CF (particularly those with PI), but there is cur-
delivery of lipase during enteral tube feeds, was shown to increase
rently insufficient data for the CFF to recommend routine EFA plasma omega-3 fatty acid levels (a surrogate marker for fat
supplementation [5,36]. In the small percentage of CF patients
absorption) 2.8-fold over placebo in a randomized controlled
who develop cirrhosis, portal hypertension, and end-stage
trial of patients with CF, though the study population was rela-
liver disease, there are additional nutritional considerations tively small [54]. It is currently approved by the United States FDA
beyond the scope of this discussion. In such a situation, careful
for adult and pediatric patients five years of age and above to
attention to liver-disease-related wasting, limited bile flow,
hydrolyze fats in enteral formula. Some patients are already using
and the risk of bleeding is essential. These patients should this modality during overnight tube feeds instead of oral PERT, but
undergo consultation with a liver specialist and will sometimes
importantly, in contrast to oral supplements, Relizorb™ only con-
require specialized administration of D-alpha tocopheryl poly-
tains lipases, without proteases or amylases. The impact of this
ethylene glycol-1000 succinate (TPGS) fat-soluble vitamin pre- formulation has not been fully defined yet, but due to this fact, the
parations for improved absorption [42,43].
authors only employ this new modality withelemental formulas.
860 T. L. RATCHFORD ET AL.

7. Conclusions extremely complicated given it is acidic, likely dysmotile, and

covered in thick mucus. Until more established data is
CF is a severe, progressive genetic disease that affects many
obtained, the authors do advocate for utilizing a polyethylene
organs of the body. It is caused by mutations in the CFTR gene,
glycol-based stool softener at least daily, and at times more,
and numerous CFTR mutations exist. Higher growth parameters
based on current knowledge and theory about the CF intes-
are associated with better pulmonary function and outcomes in
tine, as these non-absorbed, hydrophilic molecules hold water
CF, and therefore optimizing nutrition is critical in CF patients,
in the intestinal lumen and in theory dilute the high salt
especially children. Patients with CF are prone to malnutrition,
concentration and soften the thick mucus in the lumen,
growth failure, and vitamin deficiencies due to the malabsorp-
which would hypothetically improve mixing and contact of
tion inherent to the pathophysiology of the disorder, and they
chyme with enterocytes. The authors’ experience is that with a
require serial assessments of growth parameters as well as
typical adult daily dose of 17g of polyethylene glycol dissolved
clinical and biochemical evaluation for malnutrition. Patients
in 240mL of fluid then consumed in 10 min or less, patients
with CF have a large differential diagnosis for poor growth, and
often notice reduced abdominal symptoms such as bloating
multidisciplinary evaluation for this problem is essential.
and abdominal pain. Using the similar theory in terms of
Effective nutritional management generally includes the provi-
formulas (in infants as well as older patients), the authors’
sion of sufficient PERT, adequate calories for growth, fat-soluble
personal experience is that formulas closer to isotonic osmol-
vitamins, and minerals, though numerous factors must be con-
ality are better tolerated than concentrated, hypertonic alter-
sidered for the individual patient. Many patients require enteral
natives. While this observation is anecdotal, we theorize that
feedings via gastrostomy tube in order to achieve enough
due to the CF intestinal environment already being abnor-
caloric input for growth, and this therapy should be pursued
mally thick and salty as noted above, hypertonic feeds exacer-
without hesitation if it is needed. There are several recent
bate symptoms of bloating, abdominal pain, and diarrhea.
developments in novel treatments for CF that affect nutrition,
Instead, we have found that a larger volume of isotonic feed
and multiple new therapies are in clinical trials.
that provides the same caloric load is usually better tolerated.
The most exciting developments in the area of CF are the
CFTR modulators, and these treatments will likely have major
8. Expert commentary
implications in the gastrointestinal and nutritional manifesta-
Although CF remains a severe, life-threatening disease, a mul- tions of the disease in the future. However, there is no ‘cure’
titude of research and clinical developments over the years for CF at the present time, and as such, the authors stress the
has advanced our knowledge of this condition and led to importance of optimizing the gastrointestinal and nutritional
improved patient outcomes, with life expectancies greater management of these patients in addition to the pulmonary
than ever before. Despite this, many unanswered questions and multidisciplinary care they receive.
remain, particularly in areas that have historically received less
research focus in CF, such as chronic gastrointestinal issues, as
their impact on survival may have been underestimated until 9. Five-year view
more recent years, despite the fact that they tend to affect
The future of CF lies with genetic therapies. The goal of
quality of life significantly.
other CF treatments, including those in the realm of gastro-
Like early diagnosis and aggressive management of CF,
enterology and nutrition, is to restore function and alleviate
early diagnosis and aggressive management of poor growth
damage done by the causative genetic defect. However,
in CF has appropriately become standard of care. However, as
given the multitude of individual mutations that cause dis-
new correlative data emerges, there will likely be a need for
ease, as well as the heterogeneity of manifestations seen, it
establishing new parameters for routinely monitoring lean
is likely that for many individuals, these ‘supportive’ evalua-
body mass, as well as ways to increase lean mass rather than
tions and treatments will be needed for many years, and
fat mass, and further research is needed in this area.
thus we strongly advocate for continued research and
Furthermore, it is unclear as to why some infants and young
development in these areas. In gastroenterology and nutri-
children with CF and PI respond better to current nutritional
tion, it seems the most needed and forthcoming studies
management strategies than others, and further research
will be addressing the observed effects of CFTR modulators
should continue to be directed into this area. Supranormal
on both growth as well as longer term outcomes. In addi-
caloric intake (equal to or greater than 120% of estimated
tion to this, we anticipate additional study into the role of
energy requirement) and sustained normal plasma linoleic
lean body mass rather than overall body mass in relation to
acid levels have been identified in subgroups of patients
outcomes, as well as studies in CF-related gastrointestinal
with CF and PI who did successfully respond within 2 years
motility and advances in more physiologic delivery of PERT.
of diagnosis, but additional research should continue to be
focused on elucidating the mechanisms for this [55].
Optimizing the enteral delivery and absorption of nutrients
Key issues
in a markedly abnormal intestinal milieu has been and con-
tinues to be a major challenge. While malabsorption and ● Cystic Fibrosis is multisystemic disease. While the effects on
associated symptoms had been commonly attributed to sub- the lungs, liver, and pancreas are well-known, clinicians
optimal PERT dosing in the past, we have learned that “more” must be aware that the CF intestine also has a markedly
is not “better,” and improving absorption in the CF intestine is abnormal milieu, which has a significant effect on
 EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 861

malabsorption and other common gastrointestinal issues in 2. Li L, Somerset S. Digestive system dysfunction in cystic fibrosis:
these patients. challenges for nutrition therapy. Digestive Liver Disease: Official
● The effects of gastrointestinal manifestations in CF are wide- Journal Italian Society Gastroenterology Italian Association Study
Liver. 2014;46(10):865–874.
ranging, and a multidisciplinary approach involving a pul- 3. Turck D, Braegger CP, Colombo C, et al. ESPEN-ESPGHAN-ECFS
monologist, gastroenterologist, endocrinologist, dietitian, guidelines on nutrition care for infants, children, and adults with
psychologist, and social worker is very important in both cystic fibrosis. Clin Nutr. 2016;35(3):557–577.
evaluation and management of the disorder. 4. Solomon M, Bozic M, Mascarenhas MR. Nutritional Issues in Cystic
● Early identification and prompt management of CF and its Fibrosis. Clin Chest Med. 2016;37(1):97–107.
5. Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for
nutritional complications are critical, as malnutrition is a pediatric patients with cystic fibrosis. J Pediatr Gastroenterol Nutr.
consequence of the disease, and improved outcomes and 2002;35(3):246–259.
lung function are associated with better growth parameters. 6. Sullivan JS, Mascarenhas MR. Nutrition: prevention and management
● PERT is an essential therapy in CF patients. However, when of nutritional failure in Cystic Fibrosis. Journal Cystic Fibrosis: Official
Journal European Cystic Fibrosis Society. 2017;16(Suppl 2):S87–s93.
symptoms of malabsorption are present, there are several
7. Farrell PM, Kosorok MR, Rock MJ, et al. Early diagnosis of cystic
additional factors to consider other than adjustment of fibrosis through neonatal screening prevents severe malnutrition
PERT dosing. and improves long-term growth. Wisconsin cystic fibrosis neonatal
● Enteral supplemental nutrition should be discussed early in screening study group. Pediatrics. 2001;107(1):1–13.
the patient’s course and should be facilitated by the invol- 8. Munck A, Boulkedid R, Weiss L, et al. Nutritional status the first two
vement of a gastroenterologist and dietitian experienced in years of life in cystic fibrosis diagnosed by newborn screening. J
Pediatr Gastroenterol Nutr. 2018;67(1):123-130.
CF-related nutritional issues. Gastrostomy tube feeds 9. Sanders DB, Zhang Z, Farrell PM, et al. Early life growth patterns
should be utilized when long-term supplementation is persist for 12 years and impact pulmonary outcomes in cystic
warranted. fibrosis. Journal Cystic Fibrosis: Official Journal European Cystic
● The clinician should evaluate for deficiencies in macro- and Fibrosis Society. 2018;17(4):528-535.
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micronutrients in CF patients, and fat-soluble vitamins, as
2 years of diagnosis is positively associated with pulmonary status
well as minerals including sodium chloride should be pro- at 6 years of age in children with cystic fibrosis. Pediatrics. 2009;123
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New therapies, including CFTR potentiators and modulators, indexes in early life predict pulmonary function in cystic fibrosis. J
Pediatr. 2003;142(6):624–630.
are becoming increasingly available, and it is hoped that with
12. Yen EH, Quinton H, Borowitz D. Better nutritional status in early
new discoveries, nutritional outcomes will be improved in the childhood is associated with improved clinical outcomes and survival
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13. Stallings VA, Stark LJ, Robinson KA, et al. Evidence-based practice
recommendations for nutrition-related management of children
Funding and adults with cystic fibrosis and pancreatic insufficiency: results
of a systematic review. J Am Diet Assoc. 2008;108(5):832–839.
This paper was not funded. 14. Vandenbranden SL, McMullen A, Schechter MS, et al. Lung function
decline from adolescence to young adulthood in cystic fibrosis.
Pediatr Pulmonol. 2012;47(2):135–143.
Declaration on interest 15. Steinkamp G, Wiedemann B. Relationship between nutritional sta-
tus and lung function in cystic fibrosis: cross sectional and long-
J.H. Teckman is a consultant in the ‘Alpha-1’ patient community, grant itudinal analyses from the German CF quality assurance (CFQA)
reviewer and advocate for the non-profit Alpha-1 Foundation and the project. Thorax. 2002;57(7):596–601.
Alpha-1 Project. J.H. Teckman is a consultant, site investigator, and/or 16. Stephenson AL, Mannik LA, Walsh S, et al. Longitudinal trends in
grant recipient involved with the following companies; Alnylam Inc, nutritional status and the relation between lung function and BMI
Arrowhead Pharmaceuticals Inc, Dicerna Inc, Editas Pharmaceuticals, in cystic fibrosis: a population-based cohort study. Am J Clin Nutr.
Gilead Pharmaceuticals, Intellia Corp, Proteostasis Inc, RestorBio, Third 2013;97(4):872–877.
Rock Consulting, Triangle Insights, GLG consulting, and Snyder Legal. 17. Alvarez JA, Ziegler TR, Millson EC, et al. Body composition and lung
function in cystic fibrosis and their association with adiposity and
normal-weight obesity. Nutrition (Burbank, Los Angeles County,
Reviewer disclosures Calif). 2016;32(4):447–452.
18. Hanna RM, Weiner DJ. Overweight and obesity in patients with
Peer reviewers on this manuscript have no relevant financial or other cystic fibrosis: a center-based analysis. Pediatr Pulmonol. 2015;50
relationships to disclose. (1):35–41.
19. Rafeeq MM, Murad HAS. Cystic fibrosis: current therapeutic targets
and future approaches. J Transl Med. 2017;15(1):84.
20. Gelfond D, Borowitz D. Gastrointestinal complications of cystic fibro-
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