nutrients

Review
The Changing Landscape of Nutrition in Cystic Fibrosis: The
Emergence of Overweight and Obesity
Julianna Bailey 1, *, Stefanie Krick 1,2 and Kevin R. Fontaine 3

1 Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham,
Birmingham, AL 35294, USA; [email protected]
2 Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham,
Birmingham, AL 35294, USA
3 Department of Health Behavior, School of Public Health, University of Alabama at Birmingham,
Birmingham, AL 35294, USA; [email protected]
* Correspondence: [email protected]; Tel.: +1-205-778-8667

Abstract: Cystic fibrosis has historically been characterized by malnutrition, and nutrition strategies
have placed emphasis on weight gain due to its association with better pulmonary outcomes. As
treatment for this disease has significantly improved, longevity has increased and overweight and
obesity have emerged issues in this population. The effect of excess weight and adiposity on CF clini-
cal outcomes is unknown but may produce similar health consequences and obesity-related diseases
as those observed in the general population. This review examines the prevalence of overweight and
obesity in CF, the medical and psychological impact, as well as the existing evidence for treatment in
the general population and how this may be applied to people with CF. Clinicians should partner
with individuals with CF and their families to provide a personalized, interdisciplinary approach
that includes dietary modification, physical activity, and behavioral intervention. Additional research
is needed to identify the optimal strategies for preventing and addressing overweight and obesity



in CF.


Citation: Bailey, J.; Krick, S.; Fontaine, Keywords: cystic fibrosis; nutrition; obesity; overweight; body composition; body mass index (BMI)
K.R. The Changing Landscape of
Nutrition in Cystic Fibrosis: The
Emergence of Overweight and
Obesity. Nutrients 2022, 14, 1216. 1. Introduction
https://doi.org/10.3390/nu14061216
Cystic Fibrosis (CF) is a rare, life-shortening multi-system organ disease that affects
Academic Editor: Dariusz Nowak 30,000 people in the United States and 70,000 people worldwide [1]. Pulmonary failure is
the main cause of death in this population; the heavy involvement of the gastrointestinal
Received: 9 February 2022
Accepted: 11 March 2022
system creates significant nutritional impairments [2]. CF was initially called “Cystic
Published: 13 March 2022
fibrosis of the pancreas” due to the aggressive involvement of the GI system [3]. Historically,
malnutrition and underweight have been the prevailing nutritional issue in people with
Publisher’s Note: MDPI stays neutral CF (PwCF). Nutritional status has long been defined by body mass index (BMI) in this
with regard to jurisdictional claims in
patient population due to epidemiological evidence that BMI is closely correlated with lung
published maps and institutional affil-
function and, ultimately, survival. Due to the positive correlation between BMI and lung
iations.
function, the Cystic Fibrosis Foundation (CFF) has set BMI goals of at or above the 50th
percentile for children and 22 kg/m2 or higher for adult females and 23 kg/m2 or higher
for adult males with CF [4]. For this reason, and due to the history of malnutrition with CF,
Copyright: © 2022 by the authors.
most nutrition interventions have focused on increasing BMI. A high-calorie, high-protein,
Licensee MDPI, Basel, Switzerland.
high-fat diet is recommended for most PwCF, along with oral supplements and sometimes
This article is an open access article supplemental enteral feeds to help patients achieve the BMI goals associated with the best
distributed under the terms and health outcomes [5]. Aggressive nutrition support has been recommended in pediatric
conditions of the Creative Commons patients with CF to avoid/prevent malnutrition, and to promote catch up growth. Moreover,
Attribution (CC BY) license (https:// adequate nutritional status has been associated with reduced pulmonary exacerbations
creativecommons.org/licenses/by/ and improved lung function [6].
4.0/).

Nutrients 2022, 14, 1216. https://doi.org/10.3390/nu14061216 https://www.mdpi.com/journal/nutrients

Nutrients 2022, 14, 1216 2 of 18

However, overweight and obesity have emerged as an important issue in the CF

population due to advancements in therapy and increased longevity, especially in recent
years with the introduction of CF transmembrane conductance regulator (CFTR) modu-
lator therapies [7–10]. There are limited data on overweight and obesity in CF, and few
studies related to the impact of obesity on clinical outcomes in CF. The purpose of this
review is to critically examine the literature on overweight and obesity in CF, and to make
recommendations for clinical practice and future research in this area.

2. Overweight and Obesity in Cystic Fibrosis

BMI has been used to define overweight and obesity, with overweight classified
as a BMI 25–29.9 kg/m2 and obesity as BMI of ≥30 kg/m2 in adults. In children, BMI
percentiles are used to measure growth and 85–95th percentile indicates overweight with
>95th percentile indicating obesity in children [11]. In the United States, 42.2% of adults
are obese, with 9% being severely obese [12]. The prevalence of childhood obesity in
the U.S. is 19.3% [13]. Obesity is associated with the development of many chronic and
potentially life-threatening health conditions such as heart disease, cancer, and diabetes
and virtually every organ system can be adversely affected by obesity. The medical cost
associated with obesity is estimated to be USD 149 billion, making it both a serious public
health crisis and economic issue in the general population [14]. While malnutrition has
been the primary issue in CF due to increased work of breathing and malabsorption,
obesity and overweight are becoming a growing concern [15]. Dyslipidemia and insulin
resistance have been observed in the CF population; it is unknown how these factors affect
risk for development of heart disease and diabetes, and how obesity may affect risk for
development of comorbidities in CF due to the life-shortening nature of this disease [16–18].
Nutritional status has largely been defined by BMI in the CF population due to
associations between BMI and pulmonary disease. Given the changing landscape of
nutritional status in PwCF and the rise in overweight and obesity, body composition as a
predictor of pulmonary and clinical outcomes has also become an area of interest. Further
examination of body composition is merited given that the World Health Organization
defines obesity as “an abnormal or excessive accumulation of fat that poses a risk to
health” [19]. Research on obesity and body composition in the general population has
demonstrated that body fat distribution, particularly increased upper body fat, visceral
fat, and intramuscular fat, are important predictors of metabolic consequences commonly
associated with obesity [20]. Evidence suggests that PwCF tend to have lower fat-free mass
than healthy controls [21–27] and that lower fat-free mass is associated with lower lung
function in CF [21,23,28–31]. Other body composition abnormalities including ectopic fat
deposition with fatty replacement of the pancreas, central adiposity, visceral adiposity, and
normal weight obesity have been observed in CF [28,29,32–35]. Few studies have explored
the implications of increased abdominal fat and visceral fat specific to CF; however, one
cross-sectional study of adults with CF found that high levels of visceral fat in CF were
associated with decreased insulin sensitivity [36]. While associations between some clinical
outcomes and body composition exist in the literature, more studies are needed to ascertain
the role of body composition in nutritional assessment, and other clinical aspects of CF
treatment including the management of overweight and obesity.

2.1. Prevalence
Several studies have assessed the prevalence of overweight and obesity in CF. A CF
center-specific cross-sectional study in children at the Pittsburg CF Center found an in-
creased rate of overweight and obesity in children with CF, with 15% of children qualifying
as overweight and 8% of children were obese, based on BMI percentile [15]. Interestingly,
50% of the overweight children and 20% of the obese children suffered from malabsorption
caused by CF-associated exocrine pancreatic insufficiency [15]. A recent single center study
conducted in the Minnesota adult CF center found that >30% of patients were overweight
or obese between the years of 2015–2017 [37]. A longitudinal analysis of the U.S. CF Foun-
Nutrients 2022, 14, 1216 3 of 18

dation Patient Registry indicates that the prevalence of overweight and obesity increased
over the past 20 years in both children and adults with CF. Between the years of 1998 and
2017, the percentage of overweight increased from 7% to 16% and the proportion of obese
patients increased from 2% to 6%, which was noted to be a 345% increase in the number
of PwCF who are obese due to CF population increase in the registry [38]. Increased over-
weight and obesity has also been observed in the UK CF population, and in a CF genotype
typically associated with pancreatic insufficiency. An analysis of UK CF registry data for the
year of 2002 attempted to determine the prevalence of overweight and obesity in children
and adults with the most common CF mutation, DeltaF508 homozygous. Results indicated
that 9% of PwCF and the DeltaF508 homozygous genetic mutation were overweight and
1% were obese [39]. While rates seem low compared to the obesity prevalence in the general
population, this is significant because overweight and obesity are not expected in patients
who are homozygous for DeltaF508 as this genotype has historically been associated with
more severe nutritional deficiencies [40]. A cross-sectional observational study of 68 adults
and children with CF in a Greek CF center found that 13.2% of patients with CF were either
overweight or obese [35]. Analysis of a single CF center in Spain found that 6% of children
with CF were overweight and 1% were obese, and that overweight/obese status did not
provide improved pulmonary function [18]. Likewise, in Italy, a single site study of adults
with CF found that 22% were either overweight or obese [41]. In addition to cross-sectional
studies found in the literature, a longitudinal cohort study in Toronto of 909 adults with
CF and that found that the percentage of overweight and obese CF patients increased
from 7% to 18.4% between 1985 and 2011, similar to trends observed in the U.S. CF Patient
Registry [8,38]. Prevalence of overweight and obesity in CF from cross-sectional and longi-
tudinal studies in international CF samples is presented in Table 1. Given early data from
weight gain on new CFTR modulators that are available to 90% of the CF population, we
can expect these numbers to rise even further [9,42–44].

Table 1. Studies examining prevalence of overweight and obesity in CF.

Reference Population N % Overweight % Obese

42,988 across study
United States CF Registry Data,
Flume et al., 2019 [38] duration from 16% in 2017 6% in 2017
Age ≥ 2 years
1998–2017
Spain, 12 hospitals
González Jiménez et al., 2017 [18] 451 6% 1%
Age 4–57 years
Italian, multi-center
Gramegna et al., 2021 [41] Adults 321 20% 2%
Age 32–45 years
United States, single CF Center
Hanna et al., 2015 [15] Children 226 15% 8%
Age 2–18
United States, single CF Center,
Harindhanavudhi et al., 2020 [37] Minnesota 484 25.6% 6.6%
Adults
United Kingdom CF
Registry Data 1869 children 9% in adults 1% in adults
Kastner-Cole et al., 2005 [39]
Adults and children with 1181 adults and children and children
F508del mutation
Greece, single CF Center
Panagopoulou et al., 2014 [35] 68 6% 7%
Age 2–38 years
Toronto single CF Center
Stephenson et al., 2013 [8] 651 18.4% 3.3%
Adults
Australia, children from
White et al., 2015 [45] 832 8.8% 9.9%
16 inpatient hospitals
Nutrients 2022, 14, 1216 4 of 18

2.2. Etiology
2.2.1. Genetics
Multiple factors may contribute to the decreasing proportion of malnutrition and
increasing prevalence of overweight and obesity in CF. There is evidence to suggest that
some people are genetically predisposed to development of overweight and obesity [46]. In
the CF population, some studies have found that obesity occurs more frequently in patients
with less severe genetic mutations and patients who are pancreatic sufficient [8,39]. A US
CF Registry-based study conducted by Flume and colleagues found that the prevalence
of obesity was higher among individuals with CF who had class IV or class V CF causing
genetic mutations, which are typically less severe mutations. However, a recent single CF
center study in Minnesota found that overweight and obesity were present even in patients
with genotypes associated with more severe disease [37], and a UK CF Registry-based
study found that overweight and obesity were present in patients homozygous for F508del,
which is known to present a more severe phenotype and is associated with pancreatic
insufficiency [39].

2.2.2. Dietary Causes

The unrestricted high-calorie, high-fat diet that is often called the “legacy CF diet”
likely contributes to positive energy balance that promotes excessive weight gain. PwCF
have long been advised and behaviorally conditioned to consume an unrestricted high-
calorie diet with an emphasis on weight gain since childhood and have received vastly
different messaging around nutrition than the general population [4]. Indeed, studies of
diet quality in children with CF have shown intake high in saturated fat, trans fat, and total
calories but low in nutrient-dense foods such as fruits and vegetables [47]. A similar pattern
has been observed in adults with CF in a cross-sectional study that demonstrated intake
high in added sugars, refined grains, trans-fatty acids, and low intakes of whole grains
and dietary fiber [36]. Further, poor diet quality was associated with high levels of visceral
adipose tissue in this study [36]. Until recently, CF nutrition guidelines recommended
an unrestricted high-calorie diet, with little focus on nutrient density or diet quality. As
clinical care and treatments for CF have improved over the past decade, the high-calorie
CF diet may have had led to positive energy balance and excessive weight gain in a subset
of PwCF. Extended life expectancy is prompting a focus on diet quality to promote optimal
health outcomes and prevention of other chronic lifestyle diseases in CF.

2.2.3. CFTR Modulator Therapy

Highly effective drugs that treat CF at the cellular level, known as CFTR modulators,
are now available for up to 90% of the population with CF. CFTR modulators have been
shown to improve pulmonary function, quality of life, and in some cases, cause weight
gain and increase BMI. A recent systematic review concluded that the effect of CFTR mod-
ulators on anthropometric measurements is dependent on genetic mutation and modulator
formulation [48]. Ivacaftor, the first CFTR modulator approved, was available to roughly
6% of the CF population who have gating mutations and was shown to increase weight
and linear growth in children with CF [49–51]. In a long-term study of the clinical effects of
ivacaftor, Guimbellot et al. observed that the proportion of overweight increased from 16%
to 25% in adults and from 9% to 18% in pediatric patients over 5.5 years on the drug [10].
The rate of obesity remained stable in pediatric patients but increased slightly from 8% to
11% in adults [10]. A new highly effective CFTR modulator, elexacaftor-tezacaftor-ivacaftor
(ETI), is now available to up to 90% of the CF population and has been shown to increase
BMI in adolescents and adults with CF by 0.9–1.1 kg/m2 in phase III clinical trials [43,44].
A single-center retrospective study recently confirmed weight gain in adults on ETI in the
real-world setting, with an average BMI increase of 1.5 kg/m2 after 12 months on ETI [9].
Few studies have explored mechanisms of weight gain on CFTR modulators, but
decreased resting energy expenditure, increased caloric intake, and improved intestinal
absorption are postulated to play a role in adults with gating mutations taking ivacaftor
Nutrients 2022, 14, 1216 5 of 18

only [52]. One study of dietary changes on ivacaftor demonstrated that American par-
ticipants increased their fat intake significantly, while Italian participants increased both
total calorie and fat intake while taking ivacaftor [53]. This may be due to drug package
instructions that advise patients to take the drug with “a fat containing food” twice per day
while the quantity of fat that should be consumed for optimal drug efficacy is unknown.
Some evidence also indicates that children with CF who took ivacaftor showed improve-
ment, and in some cases, reversal of exocrine pancreatic insufficiency [54–56]. Improved
pancreatic function likely plays a role in weight gain in children who take ivacaftor.
It is important to understand whether weight gain on CFTR modulators is due to
fat mass or lean body mass accrual. There are little data on body composition changes
on CFTR modulators, but one study of adults who took ivacaftor found an increase in
both fat mass and fat-free mass as measured by DEXA after 3 months on the drug [52].
Another study found an increase in fat mass using bioelectrical impedance analysis after
28 days on ivacaftor [57]. In a long-term open label extension study of ivacaftor, King et al.
found that both weight and fat mass significantly increased after 6 months of treatment
and, at two years on the drug, 64% of weight gained was fat mass. Additionally, 25% of
participants were classified as overweight and 10% were obese by the end of the two-year
study [58]. More studies of longer duration are needed to examine body composition and
fat distribution changes on CFTR modulators in the setting of unintended weight gain and
the development of overweight and obesity on these drugs.

2.2.4. Social Determinants of Health

Social determinants of health are defined as environmental conditions that affect health
and quality of life outcomes and risks [59]. Limited access to healthy food correlates with
other unmet needs that indicate poverty. Poverty and food insecurity are both associated
with obesity in the general population [60,61]. Health disparities related to poverty or low
socioeconomic status (SES) have been documented in CF and affect survival, CF-related
clinical outcomes, and access to optimal healthcare for CF [62–64]. Low SES is associated
with obesity in the general population but socioeconomic factor contributions to overweight
and obesity in the CF population have not been explored. Food insecurity and limited
access to healthy food could increase risk for overweight and obesity in the population due
to reliance on high-calorie convenience foods that lack nutrient density. Additionally, PwCF
spend an average of 2–3 h per day on a complex medical treatment regimen, which leaves
little time for healthy meal planning, particularly in the setting of food insecurity that limits
access to healthy food. It is reasonable to suspect that a similar association between obesity
and poverty and food insecurity observed in the general population may exist in CF, but
national CF Registry-based studies are needed to understand the role of social determinants
of health in the development of overweight and obesity in the CF population. Additional
research could provide data to create targeted interventions to prevent over-nutrition in
subsets of the CF population experiencing socioeconomic hardship.

3. Consequences of Overweight and Obesity in Cystic Fibrosis

3.1. Lung Function
There is a strong positive association between BMI and lung function in the CF popu-
lation [2]. A large Canadian CF Registry analysis found that while overweight and obesity
were associated with an increase in lung function, the magnitude of the increase was signif-
icantly less in the obese group than in the adequate-weight reference group [8]. Emerging
evidence suggests that overweight and obesity may not provide benefit with respect to
pulmonary function and could even be detrimental. In a single-center cross-sectional study
conducted by Hanna et al., no associations were observed with overweight/obese status
and lung function, prompting the authors to conclude that overweight and/or obesity does
not confer pulmonary benefits in CF [15]. Several other studies examining prevalence and
outcomes of obesity in CF have found that overweight and obesity were not protective
with respect to lung function [8,15,18,65]. Additionally, emerging evidence suggests that in
Nutrients 2022, 14, 1216 6 of 18

children with CF who are pancreatic sufficient, a BMI > 85th percentile has a detrimental
effect on pulmonary function [66]. Large national registry-based studies are needed to
determine longitudinal associations between higher BMI and pulmonary outcomes in the
CF population.

3.2. Cardiometabolic Parameters

Few studies have addressed the effect of obesity on other comorbidities in CF. Shorter
life expectancy has typically not allowed for patients with CF to live to the age where
obesity-associated comorbidities such as heart disease, cancer, and type 2 diabetes would
emerge. Additionally, at least one study estimates that up to 50% of adults with CF
develop CF-related diabetes, which is a unique disease entity distinct from both type 1
and type 2 diabetes, but with features of both insulin deficiency and insulin resistance [16].
The endocrine abnormalities inherent to CF make understanding the association between
obesity and development of diabetes more difficult to assess in this population. However,
a cross-sectional study by Coderre and colleagues found that 13% of adults with CF had
a BMI > 25 kg/m2 and these overweight/obese patients had higher fasting insulin, total
cholesterol, and LDL cholesterol than patients with CF at lower BMI. They also found
that LDL cholesterol and insulin area under the curve were associated with lower lung
function [67]. In a comparison of underweight, normal weight, and overweight PwCF
to determine differences in insulin levels, insulin response, and prevalence of diabetes,
5.5% of patients were overweight and overweight patients had higher fasting insulin,
higher insulin resistance (HOMA-IR), and higher insulin levels during an oral glucose
tolerance test [65]. Authors concluded that overweight patients with CF may be at increased
risk for the development of diabetes [65]. Dyslipidemia has also been observed in the CF
population and studies have found a positive association between total cholesterol and
triglyceride levels and BMI in the CF population [8,67–70]. In a recent study, ETI was shown
to increase total cholesterol, HDL, and LDL in adult patients with CF-related diabetes. The
implications of dyslipidemia in PwCF are not clear, and the role of dietary intervention
in CF dyslipidemia is unknown [9]. More longitudinal research is needed to understand
the association between overweight and obesity in CF and how this affects risk for the
development of diabetes and cardiovascular disease.

3.3. Lung Transplantation

Lung transplantation is a treatment option for end-stage pulmonary diseases including
CF. Large database evidence suggests that both malnutrition and overweight are associated
with increased risk of death following a lung transplant. Currently, class II or III obesity
(BMI ≥ 35 kg/m2 ) is considered an absolute contraindication to lung transplant, and class
I obesity (BMI 30–34.9 kg/m2 ) is considered a relative contraindication. In a recent study of
546 lung transplant patients, patients who were overweight or obese had a significantly
higher mortality rate. Of note, only two of the patients who had CF were overweight and
none were obese. More research is needed to understand how overweight and obesity
affect lung transplant outcomes in CF, and assessing body fat distribution may be especially
important as abdominal and visceral fat can play a role in restrictive lung disease [71].

3.4. Weight Stigma and Psychological Consequences

Obesity is common in the general population but is a highly stigmatized condition
in many settings including the medical environment. Evidence suggests that people
with obesity experience prejudice, derogatory comments, and that in some cases, health
care professionals hold negative perceptions of patients who are overweight or obese.
Patient experience of weight stigma can also lead to increased stress and subsequent
avoidance of clinical care [72]. A recent systematic review of the impact of weight stigma in
overweight and obese individuals found that weight stigma was positively associated with
cortisol levels, diabetes risk, eating disturbances, depression, anxiety, body image issues,
and was negatively associated with self-esteem [73]. In the general population, weight
Nutrients 2022, 14, 1216 7 of 18

stigma has been associated with decreased motivation to change eating patterns and less
healthy eating behaviors, which could lead to negative health consequences [74]. While
there are no studies related to weight stigma in overweight and obese PwCF, there is a
growing body of evidence related to body image disturbances and even eating disorders
in this population [75–77]. Clinicians should therefore take a sensitive and empathetic
approach when having discussions about overweight and obesity, and be cognizant of
the psychological consequences of weight stigma. Additionally, it would be beneficial to
include the CF team social worker and/or psychologist early on in the care of these patients
to address the mental health impact of overweight and obesity.

4. Treatment Strategies
Management of overweight and obesity in the general population typically involves
weight loss given evidence that a reduction of 5–10% body weight can reduce the risk
of cardiovascular disease, improve lipid panels, decrease blood pressure, and decrease
risk of diabetes [78,79]. Even a sustained weight reduction of as little as 3–5% has been
associated with some positive health benefits and reduced health risk [80]. Weight loss in
overweight and obesity can be effectively achieved by creating negative energy balance
through dietary modification to reduce energy intake paired with physical activity to
increase energy expenditure, and supported by behavioral counseling to facilitate lifestyle
change [81,82]. Studies show that this approach can produce a 3–5% body weight loss
that is associated with an improvement in health parameters [83]. Other markers of health
can include cardiometabolic parameters such as lipid panels, blood pressure, diet quality,
eating behaviors, hemoglobin A1c (in diabetic patients), body composition parameters, and
quality of life. When lifestyle modification is unsuccessful, medication and even surgical
management may be necessary.
To our knowledge, no studies exist regarding treatment strategies for overweight
and obesity in in CF. Studies conducted thus far suggest some associations between over-
weight/obesity and comorbidities in CF, worse lung transplant outcomes, dyslipidemia,
and increased diabetes risk with higher fasting insulin levels. Therefore, further work is
needed to better understand the etiology, consequences, and treatment and prevention
strategies for PwCF who are overweight and obese. It is important to have a full evaluation
by all members of the multidisciplinary CF care team when a patient has unintended weight
gain that results in overweight or obesity. Causes of weight gain such as medications and
other disease processes should be ruled out before pursuing interventions for overweight
and obesity management. While research is conducted to identify the optimal approach to
overweight and obesity in CF, it is reasonable to utilize evidence-based methods for the
general population presented in this section.

4.1. Dietary Intake Recommendations

The CF Foundation has not formally updated CF Nutrition Guidelines since obesity
and overweight emerged as a significant issue or since highly effective CFTR modulators
recently became available for most of the CF population. However, several organizations
have created evidence-based guidelines in recent years, which are presented in Table 2.
Most recently, the Academy of Nutrition and Dietetics (AND) published guidance based
on a systematic review that suggests that there is no evidence to support that PwCF have
any benefit from consuming a dietary pattern outside of what is recommended for the
general population [84]. This guideline also emphasizes just as some patients with CF
experience under-nutrition, some patients may require caloric reduction with a focus on
improving diet quality given that undesired weight gain, overweight, and obesity have
been reported in a subset of the CF population, especially with CFTR modulator use.
Both the Australia and New Zealand CF Nutrition Guideline and the AND CF Nutrition
Guideline emphasize taking an individualized approach to nutrition care based on patients’
genetic mutations, clinical status, laboratory values, personal health goals, nutrition status,
culture, and food preferences [84,85]. The AND guideline suggests a diet rich in whole
Nutrients 2022, 14, 1216 8 of 18

grains, fruits, vegetables, seafood, legumes, lean protein, nuts and beans, and low-fat
dairy as these foods have been associated with positive health outcomes in the general
population [84].

Table 2. Summary of cystic fibrosis nutrition guidelines.

Guideline Reference Total Calorie Intake Macro-Nutrient Balance Overweight/Obesity

110–120% of
35–40% of calories from fat
Cystic Fibrosis estimated energy
40–45% of calories from carb N/A
Foundation, 2008 [4] requirements for general
20% of calories from protein
population
20% of calories from protein; “We suggest adjusting energy intake
110–120% of energy
notes lack of evidence for upward to achieve normal growth
ESPGAN, 2016 [86] requirements for same age
recommending and nutritional status while
healthy children and adults
macro-balance avoiding obesity” [86]
110–200% of the High BMI in Pediatrics:
population-based energy Overweight: BMI 85th to <95th BMI
Thoracic Society of requirements Obese: >95th percentile
Upper limit of 25% of
Australia New Zealand, emphasizing frequent RD High BMI in Adults: ≥27 kg/m2
calories from protein
2018 [85] assessment and AND/OR unintentional weight gain
individualized energy from previously acceptable
intake goals BMI of >5 kg within a year [85]
“For individuals with CF who are
110–200% of the overweight or obese, it is reasonable for
population-based energy the RDN or international equivalent to
“Macronutrients in same
Academy of Nutrition and requirements advise an age-appropriate diet that
percentage distribution as is
Dietetics CF Nutrition emphasizing RD frequent emphasizes foods associated with
recommended for the typical,
Guideline, 2020 [84] assessment and positive health outcomes in the general
age-matched population”
individualized energy population, with energy needs adjusted
intake goals to achieve or maintain normal growth
(pediatrics) or BMI status (adults).” [84]

In the general population, a deficit of 500 calories per day can produce weight loss
of one pound per week [87]. Negative energy balance may be achieved through diet
alone or through a combination of diet and exercise. Evidence suggests that a variety of
dietary patterns can be effective for calorie reduction including low carbohydrate, low
fat, portion control, and the Mediterranean diet pattern with calorie restriction [81,82,88].
Other dietary trends for weight loss are gaining popularity in the general population,
including time-restricted plans such as intermittent fasting; however, there is currently no
evidence to suggest efficacy in the CF population. Given that the best predictor of weight
loss is adherence to a chosen dietary plan, it is important to select the diet best suited
for the individual in order to promote the sustainability of dietary patterns and lifestyle
changes [89]. PwCF have been counseled to eat a high-calorie diet since early childhood, so
clinicians should recognize that shifting a dietary intake will take time and often trial and
error to find the pattern that works best for each individual. Small incremental changes
may be useful to build confidence and avoid overwhelming patients [90]. Table 3 presents
suggestions for modifications to the legacy CF diet adapted from the Academy of Nutrition
and Dietetics Evidence Based Guideline for Nutrition in Cystic Fibrosis and the Dietary
Guidelines for Americans with the goal of reducing calories and increasing nutrient dense
foods and foods known to promote health and reduce the risk of chronic disease.
Nutrients 2022, 14, 1216 9 of 18

Table 3. Dietary modifications for a generally healthful eating pattern.

Food Group Recommended Foods Foods to Consider Reducing

Whole grains (at least half of grains Refined Grains
should be whole grains). • White breads
• Whole wheat bread, buns, rolls, • White rice
tortillas, and crackers • Biscuits
• Whole wheat pasta • Cakes
• Brown rice Added sugars
Carbohydrates
• Wild rice • Soda
• Quinoa • Sweetened Coffee and tea
• Oats • Fruit drink and lemonade
• Barley • Many breakfast cereals
• Whole grain cereals • Granola bars
• Deserts and candy
Unsaturated Fats Saturated fats
• Vegetable oils • Butter and stick margarine
Fats • Nuts, nut butters • Heavy Cream
• Fish • Cream cheese
• Avocado
Lean Meats
Fatty meats
• Poultry
• Beef ribs
• Eggs
• Sausage
Protein • Beans, peas, lentils
• Processed meats
• Seafood
• Fried meats
• Soy products
• Nuts and Seeds
Whole Fruits
• Berries
• Melons
Fruits • Citrus Fruits (oranges, Juices that are not 100% fruit juice
grapefruit, limes)
• Other fruits (apples, banana,
pears, apricot, etc.)
Vegetables of all types including
• Dark green vegetables (spinach,
kale, broccoli)
• Red and Orange vegetables
Vegetables (peppers, squash, carrots) Fried vegetables
• Starchy vegetables (potatoes, corn,
yucca, jicama)
• Beans, peas, lentils
• Other vegetables (sprouts, cauliflower,
asparagus, eggplant, etc.)
Fat-free low-fat dairy
• Skim milk Full-fat dairy:
• 1% (low fat) milk • Whole milk
Dairy • Low-fat or fat-free yogurt • Full-fat yogurt
• Cheeses • Full-fat cheeses
• Non-dairy alternatives such as
soy milk
Additional resources on following for healthful diet plan:
www.choosemyplate.gov (accessed on 14 December 2021)
www.dietaryguidelines.gov (accessed on 14 December 2021)
Adapted from data found in Academy of Nutrition and Dietetics CF Nutrition Guidelines and the Dietary
Guidelines for Americans.

In considering dietary change recommendations for PwCF as overweight and obesity

emerge, it should be noted that malnutrition still exists in subsets of the CF population,
Nutrients 2022, 14, 1216 10 of 18

particularly in those who are not eligible to take CFTR modulators due to their genetic
mutations and in patients with advanced lung disease. PwCF who also experience malnu-
trition will likely continue to require a nutrient-dense high-calorie diet to optimize nutrition
status. The broad spectrum of nutrition status observed in CF currently highlights the
need for highly individualized nutrition therapy. The CF Care Team Registered Dietitian
should work carefully with patients in co-producing customized nutrition care plans to
help patients meet personal goals and optimize health outcomes, based on individual
clinical status, cultural considerations, and food preferences. Emphasis should also be
placed on screening for food insecurity and other social determinants of health that could
impact patient’s ability to afford healthy foods. Registered Dietitians can assist patients
in planning healthful meals and eating patterns that are affordable and should work in
tandem with the CF Social Worker and other care team members to provide resources to
improve food access for patients experiencing food insecurity.

4.2. Physical Activity

While diet is a crucial element in the management of overweight and obesity, a
multidisciplinary lifestyle intervention is recommended [91]. Exercise is an important
component of comprehensive lifestyle plans to treat overweight, obesity, and associated
comorbidities. Regular physical activity has been shown to assist in creating negative
energy balance for weight loss and improve cardiometabolic risk factors [92]. In the
general population, it is recommended to participate in 150 min per week of moderate
physical activity or 75 min per week of vigorous activity. To promote weight loss in the
absence of dietary changes, 225–420 min of exercise is recommended. However, physical
activity paired with reduced caloric intake is recommended as this strategy is more likely
to promote weight loss [93]. Research has also consistently demonstrated that physical
activity is necessary for weight loss maintenance in the general population [80]. Aside
from weight loss, regular physical activity is associated with reduced risk of cardiovascular
disease and diabetes in obese individuals, independent of weight loss [92]. In the CF
population, physical activity, particularly strength training, is an important component
of exercise plans in order to promote preservation and accrual of lean body mass [94],
which is associated with improved pulmonary function in this population. Additionally,
exercise in CF also provides additional benefits beyond weight management, including
increased aerobic and pulmonary capacity and airway clearance [95]. Further, exercise can
provide mental health benefits that could combat anxiety and depression associated with
overweight and obesity [96]. The CF Care Team Physical Therapist is an invaluable resource
in creating customized exercise plans to help patients meet their personal health, weight,
and body composition goals and that synergize with the nutrition care plans provided by
Registered Dietitians.

4.3. Behavioral Interventions

Comprehensive lifestyle interventions for overweight and obesity include dietary
intervention, physical activity, and behavioral approaches to lifestyle change [97]. A sys-
tematic review that defined successful weight loss interventions for obesity as ≥5% initial
body weight loss maintained at 12 months found that 92% of successful interventions
included a behavioral component [82]. Intensive behavioral therapy (IBT) for obesity that
includes nutritional guidance and exercise has been shown to produce significant weight
loss, lower blood glucose levels, decrease waist circumference, and decrease blood pressure.
Additionally, IBT decreased the development of diabetes by 50% in patients who had
elevated blood glucose at baseline [98]. Many behavioral change theories, models, and
strategies provide an evidence-based approach to changing behaviors related to energy
balance in the treatment of overweight and obesity. Cognitive behavioral therapy (CBT)
and motivational interviewing (MI) are two modalities of behavioral change that have been
used with success in obesity treatment [81,99]. CBT involves such skills as self-monitoring,
goal setting, problem solving, and stimulus control [81]. MI is an approach that emphasizes
Nutrients 2022, 14, 1216 11 of 18

partnership for a client-driven lifestyle change intervention [100]. Many different behavior
change models exist and a variety of combinations of behavioral techniques and strategies
can be used to facilitate behavior change.
The intensity of the comprehensive lifestyle intervention seems to have an impact on
the efficacy of behavioral interventions for the management of overweight and obesity.
Research has shown that 14 sessions in a 6-month time frame led to more weight loss than
a less frequent intervention of 12 or less sessions in 6 months [97]. It should be noted that
most patients with CF see their care team in the clinic once every 3 months, and that more
frequent multidisciplinary visits that provide comprehensive lifestyle intervention-focused
on management of overweight and obesity may be warranted. Telehealth and home-based
interdisciplinary lifestyle interventions may be an option for increasing frequency of visits
centered around treatment of overweight and obesity, particularly for patients who live far
away from their CF care centers.
Successful behavioral interventions targeting BMI in children with CF have been
conducted, although these interventions are typically focused on normalizing growth and
promoting weight gain. These interventions in the pediatric CF population have involved,
with strong parental support and participation, implementing a behavioral intervention in
combination with nutrition education, and this has been found to be more effective than
nutrition education alone [101]. These behavioral nutrition interventions focus on positive
reinforcement and promoting positive mealtime behaviors to prevent growth decline in
children with CF. It is possible that these behavioral intervention strategies could potentially
be used to prevent the development of overweight and obesity in children with CF.
Only one behavioral nutrition intervention conducted in adults with CF was identified
in the review of the literature. This randomized controlled trial was a Social Cognitive
Theory home-based behavioral intervention called “Eat Well with CF” and had a duration
of 10 weeks. While this intervention was successful in improving self-efficacy scores related
to nutritional self-management, there was no significant change in BMI or quality of life at
the end of the intervention [102]. Self-efficacy is believed to be crucial for facilitating and
maintaining behavioral changes [100]. While this intervention did not produce a significant
change in BMI, it is possible that the improvement in self-efficacy could be an early indicator
of behavioral change, especially given the short duration of the intervention [102]. It is
also possible that early changes in body composition occurred but were not captured by
measuring BMI only. Home-based behavioral interventions that involve both nutrition and
physical activity components could be an avenue for increasing the frequency and intensity
of multidisciplinary weight management interventions, especially given that telehealth is
growing in popularity, with several studies documenting a high level of patient satisfaction
and positive experience of telehealth care in CF [103,104].

4.4. Weight-Neutral Approaches

While weight loss is the most common goal in the treatment of overweight and obesity
due to associations with improved cardiometabolic outcomes, it is unknown if the benefits
associated with a 5–10% body weight loss in the general population translate to PwCF.
Given that normal weight obesity and lean body mass depletion have been documented
in CF [29], it is unclear if weight loss interventions for overweight and obese individuals
with CF will result in predominantly fat loss and could cause further reduction in lean
body mass stores. Body image issues and eating disorders have been documented in CF,
and this population deals with an intense focus on weight patterns and BMI throughout
their lifespan, due to the association between BMI and pulmonary function and guideline
recommendations based on BMI and growth [77]. There is also some evidence that sug-
gests that the influence of eating experiences in childhood are sustained into adulthood in
CF [99]. For these reasons, some individuals may instead prefer to focus on other markers
of health as outcomes, rather than weight, when designing a plan to address overweight or
obesity and related health consequences. The Health at Every Size® (HAES® ) approach is a
weight-inclusive model that focuses on improving physical, behavioral, and psychologi-
Nutrients 2022, 14, 1216 12 of 18

cal parameters rather than promoting weight loss. This method also places emphasis on
body acceptance and improving the individual’s relationship with food [105,106]. HAES®
has been gaining popularity in the general population and has been studied regarding
overweight and obesity. A recent systematic review of randomized controlled trials in over-
weight and obese individuals found that the HAES® approach is associated with improved
quality of life, improved cardiovascular endpoints, increased physical activity, reduction
in disordered eating, reduction in binging as well as improved diet quality [107]. Despite
the weight-neutral approach utilized, some studies have demonstrated reduction in BMI,
waist circumference, and fat loss as a result of the HAES® interventions [108]. While there
are no data on the efficacy of HAES® in CF, clinicians should be aware of this approach as
individuals with CF who have a history of body image disturbances or disordered eating
may prefer a weight-neutral approach to addressing the health consequences associated
with the development of overweight and obesity. More research is needed on compre-
hensive health behavior interventions, including weight-neutral approaches to improve
cardiometabolic outcomes and quality of life in the CF population.

4.5. Medical and Surgical Treatment

When lifestyle approaches are ineffective, pharmacological approaches are recom-
mended to treat overweight and obesity in the general population when BMI is >30 kg/m2
or >27 kg/m2 with comorbid conditions in adults [109]. Several drugs are approved by the
FDA to treat obesity and include orlistat, lorcaserin, liraglutide, topiramate/phentermine,
naltrexone/bupropion, and newly approved semaglutide [110]. In addition, prescription
appetite suppressants are available and include phentermine, benzphetamine, diethyl-
propion, and phendimetrazine. It should be noted that appetite suppressants are only
approved for short-term use of 12 weeks or less in the general population. Orlistat, Li-
raglutide, and setmelanotide are the only drugs approved for use in adolescents. However,
setmelanotide is only approved for three specific rare genetic conditions which do not
include CF. None of these drugs have been studied in CF and their use should be carefully
considered by the medical team, weighing the risks and benefits with patients and their
families. Of note, use of Orlistat may not be ideal in PwCF who also have pancreatic
insufficiency as this could compound malabsorption and lead to vitamin and essential fatty
deficiencies in this population that is already at high risk of micronutrient deficiencies.
A variety of bariatric procedures are available for the management of obesity and
include surgical (gastric bypass, gastric banding, sleeve gastrectomy) and non-surgical
(intragastric-balloon) options. Bariatric procedures are considered in the general population
when BMI is ≥40 kg/m2 or BMI ≥ 35 kg/m2 with one or more severe obesity-related
complications that can be improved with weight loss [109]. There currently is no evidence
on outcomes regarding bariatric procedures to treat obesity in CF, and this could lead to
micronutrient deficiencies and worsened gastrointestinal issues, particularly in patients
who have exocrine pancreatic insufficiency. Given what is known about nutrition risk in the
CF population, bariatric surgery may not be an ideal option for PwCF until more evidence
is available.

5. Discussion
Nutrition status as measured by BMI is closely linked with pulmonary outcomes and
survival in CF [4]. As life expectancy continues to increase in this population with the use of
CFTR modulators, non-traditional nutrition issues have emerged, and overweight/obesity
have become areas of interest in CF clinical care and research. Studies indicate that over-
nutrition is increasing in CF, and this has been linked to insulin resistance and other
hormonal disturbances, which are postulated to play a role in development of diabetes
and the trend of increased central fat distribution observed in this population [65,67].
Additionally, central adiposity, visceral adiposity, and normal weight obesity have been
documented in CF and could have negative health consequences [28,33–35].
Nutrients 2022, 14, 1216 13 of 18

Additional perspective is needed to determine if excess weight and adipose tissue

distribution in CF are causally related to pulmonary and cardiometabolic outcomes. Specif-
ically, additional studies are needed to determine the interplay between central adiposity
and CF-related endocrine, metabolic, and pulmonary outcomes. Given the association
between fat-free mass and lung function in CF, future research should also focus on explo-
ration of the causes and predictors of decreased fat-free mass so that interventions can be
developed to promote accrual of lean body mass and reduction in central adiposity, regard-
less of BMI status, in PwCF. While weight loss is a common goal of obesity intervention
success, clinicians should also track body composition changes to ensure that lean body
mass is preserved and optimized during weight reduction.
The care team should be cognizant of the stigma associated with overweight and
obesity and the psychological impact of undesired weight gain. It should be noted that some
individuals with CF may prefer weight-neutral interventions that place emphasis on health-
promoting behaviors and repairing their relationship with food rather than weight loss as
their main goal. Collaborating with the CF care team Social Worker and/or Psychologist is
advised, both for support around these issues and assistance with behavioral strategies to
promote optimal health and wellbeing during weight management interventions.
There is limited evidence on the optimal diet for PwCF, especially in the setting of new
highly effective CFTR modulators and the development of overweight and obesity in this
population. Caloric deficit is necessary for weight loss, and many dietary approaches have
been shown to promote weight reduction in the general population. The sustainability
of any intervention relies on an individual’s ability to adhere to the chosen regimen. It is
therefore important to take an individualized approach to nutrition care and weight man-
agement plans, and it is the role of the CF care team Registered Dietitian to partner closely
with PwCF and their families to determine a customized nutrition care plan that is the best
fit for patient preferences, culture, and clinical status. Registered Dietitians should also
closely collaborate with the CF team Physical Therapist and Social Worker/Psychologist to
create a comprehensive lifestyle approach to address overweight and obesity that works
for each patient’s individual needs. When these comprehensive lifestyle interventions
are unsuccessful, medical management of obesity may be considered in overweight and
obese individuals with CF. Given the paucity of evidence regarding weight loss drugs and
bariatric surgery in CF, clinicians should carefully weigh the risks and benefits of medical
management considering patient and family goals and only pursue those interventions in
highly specialized centers.
Additional research is needed to determine the optimal dietary pattern for PwCF,
particularly in the setting of overweight and obesity. Research should also explore the
efficacy of different dietary patterns as well as weight-neutral approaches in improving
cardiometabolic outcomes independent of weight loss in PwCF who are overweight or
obese. Qualitative studies that explore patient and family attitudes and perceptions of
their weight status and body composition, as well as what would make effective weight
management interventions in CF, are also warranted. Using patients and family voices
combined with emerging scientific evidence to guide interdisciplinary behavioral nutrition
interventions for weight management is recommended.

6. Conclusions
A comprehensive interdisciplinary approach to lifestyle change, including nutrition
care plans, enjoyable customized exercise, and behavioral strategies, is necessary to address
the new challenge of overweight and obesity in CF. The CF Care Team should take a sensi-
tive, highly individualized approach to enhance the sustainability of lifestyle interventions
to address overweight and obesity, as well as partnership in care. Expanding the research
on overweight and obesity in CF is necessary to determine the impact on cardiometabolic,
pulmonary, and quality of life outcomes, and to determine optimal behavioral nutrition
interventions for clinical practice as longevity continues to increase in this population.
Nutrients 2022, 14, 1216 14 of 18

Author Contributions: Conceptualization, J.B., S.K. and K.R.F.; writing—original draft preparation,
J.B.; writing—review and editing, S.K., K.R.F. and J.B.; supervision, K.R.F. All authors have read and
agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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