Introduction:
Although advances in cystic fibrosis (CF) care with the development,
availability, and use of CF transmembrane regulatory conductance channel
(CFTR) modulators have changed the disease trajectory, there continues
to be a need for increased understanding related to nutrition and
gastrointestinal disease for people with CF (PwCF). Nutrition has always
been a cornerstone of CF care due to pancreatic insufficiency (PI) and
the need for pancreatic enzyme replacement therapy (PERT), however many
questions continue to remain unanswered. Pancreatic insufficiency can
lead to decreased fat absorption (even with PERT) and reduced nutrient
intake, thus understanding optimal PERT doing, use of supplements and
knowledge regarding deficiencies can help improve overall care.
Gastrointestinal health goes beyond nutrition to include the microbiome,
an area of rapidly expanding research that is linked to alterations in
nutritional outcomes. In addition, liver disease in CF is currently
being redefined with recent longitudinal studies and advances in
technology adding to our understanding. This review will cover
publications related to gastrointestinal health, including PERT dosing,
nutritional deficiencies and new supplements, intestinal microbiome, and
liver disease.
NUTRITION
Nutritional management of CF starts with determination of pancreatic
status (PI or PS). Poli et al.1 describes infants with
CF who, despite having PI levels of fecal elastase at diagnoses, and
thus starting pancreatic enzyme replacement therapy (PERT), were found
to have normal fecal elastase (FE) levels at 2, 4, 5 and 6 years of age.
The authors bring to light the importance of evaluating both CF genotype
and fecal elastase (FE) measurements together in context of genotypic
norms. All of the genotypes (F508del/2789 + 5G > A,
F508del/R1066H, and M1T homozygous) were shown to have low levels of PI
on review of databases or review of the medical literature.
If patients with CF are found to be PI, the optimal dosing for PERT is
still up for debate and an area for further research. The MyCyFAPP has
been developed to help with self-management of gastrointestinal
concerns2. The app facilitates dosing of PERT via an
algorithm that assigns optimal PERT doses based on food groups. Doses
ranged from 1000-4000 lipase units/gram of fat and were based on a prior
in vitro CF digestion model. Additionally, the MyCyFAPP, had an
abdominal symptom diary, links to online tools, and educational modules.
In a 6-month prospective, multicenter study of 148 patients, between the
ages of 24 months and 18 years, use of MyCyFAPP was shown to improve
quality life as measured on the CF PedsQL-GI. Patients >12
years of age were able to participate in the study independently.
Patients had statistically significant improvements on the CF PedsQL-GI
at 6 months, but not at three months, while parents reporting for their
children ≤12 years of age had improvements at 3 months which were
sustained through 6 months. Both patients and parents reported that they
would want to use the app in their daily lives independent of the study.
To specifically evaluate the PERT dosing algorithm, 58 patients had
measurement of coefficient of fat absorption (CFA) at baseline and after
use of the MyCyFAPP3. Although the CFA remained
unchanged, the range of PERT dosing was reduced (1447-3070 LU/g fat
versus 1783-2495 LU/g fat). Those with a low CFA (≤90%) at baseline had
a significant improvement with the MyCyFAPP dosing, from 86.3% to 94%
(p=0.031), due to improved adherence to recommended PERT dosing with
consistent use of the app during the study period. However, it is
difficult to determine if improvement in CFA was due to alternative
dosing recommended by MyCyFAPP alone or simply improved adherence to
PERT. Based on the results of the study, the authors suggest increasing
the PERT dosing range to 1000-4000 LU/g of fat but recognize that longer
periods of observation with more subjects are required to confirm
results and make universal recommendations.
Another study looking at fat absorption, evaluated a novel nutritional
supplement, Encala™. Encala™ is a readily absorbable structured lipid
made of a backbone of lysophosphatidylcholine (LPC) which optimizes
dietary fatty acid absorption in the small intestine, enhances transfer
of fatty acid into the lymphatic system and improves fatty acid
retention in the mucosa4. Encala™ enhances absorption
of long-chain triglycerides and the two essential fatty acids, linoleic
and linolenic acid5. This unique supplement is a
taste-neutral powder that is mixed with foods and beverages, is water
soluble, does not require lipase for digestion/absorption, and has
previously shown safety and tolerability. The study of Encala™ effect on
baseline CFA was undertaken in children with CF age 5-17.9 years of age
in a double-blind placebo trial with 1:1 randomization. Patients with CF
who had a low CFA (<88%) at baseline were found to have
improved CFA (78.9±7.5% to 86.3±6.7%, p=0.002), a decrease in stool
fat loss and no change in dietary fat intake, while the high CFA group
had no changes in the same parameters. In addition, patients with low
CFA showed significant improvements in total plasma fatty acid
concentration (20%, p≤0.005) and anthropometrics (height-for-age
z-score (0.06 ±0.08), weight-for-age z-score (0.17±0.16), and BMI
z-score (0.20±0.25) with increases in all parameters (p≤0.002) over a
3-month period. The data is encouraging for the use of Encala™ to
optimize fat absorption above and beyond the capabilities of PERT.
Although the nutrition focus for CF is often on malnutrition due to
malabsorption, other concerns are also being studied, such as
micronutrient deficiency and the emerging concern of obesity. A cross
sectional study (the Dietary Intake Study in cHildren (DISH), evaluated
the dietary intake of 82 Australian children with CF compared to 82
healthy age and sex matched controls6. Children with
CF consume more calories/energy, with increased absolute consumption of
all micronutrients, except Vitamin C and folate. When adjusted for
energy intake, CF children consumed less micronutrients per 1000 kcal
except in Vitamin A, sodium, calcium and phosphorus. A strong
relationship with age and suboptimal micronutrient intake was seen, such
that by high school, children with CF failed to meet the recommended
daily intake amount for most key micronutrients.
Harindhanavudhi et al.7 evaluated the prevalence and
factors associated with overweight and obese adults with CF at the
University of Minnesota between January 2015-January 2017. Out of 484
adults, 25.6% were found to be overweight and 6.6% were obese.
Specifically, 25% of those with a severe genotype (defined based on
gene expression or protein function), were overweight/obese. Of those
who were overweight/obese, there was a higher prevalence of hypertension
(31%/25% versus 17%, p=0.01), higher total cholesterol,
LDL-cholesterol, and triglycerides, when compared to normal weight CF
adults. Lung function was higher in overweight/obese patients (78-81%
versus 59% [underweight] 70% [normal weight],
p<0.0001), with a threshold effect beyond a BMI of 28-29 kg/m2
whereby no further increases in FEV1 were seen.
INTESTINE
Case reports can be instructional and thought provoking for clinicians
when they are presented with similar scenarios. Several case reports
published this year are outlined in Table 1 with specific lessons
learned highlighted.
The gut microbiome is defined as the diverse collection of microbial
cells, their genetic material and the surrounding gut environmental
conditions. The microbiome is an active participant in host physiology
including energy metabolism, establishment and maintenance of the
intestinal barrier, and immune system development. The microbiome
undergoes changes over time, influenced by age, immune maturation, and
environmental factors like diet, exercise, and antibiotic exposure.
Dysbiosis occurs when there are significant changes to the composition
of the microbiome in an individual relative to healthy individuals.
Dysbiosis can lead to the development of diseases. For a growing number
of diseases, an altered microbiome is not just a marker of disease, but
also actively contributes to pathology. Not only are the number of
microbes present important, the diversity or variety of species
composition also accounts for the function of the gut microbial
community12. In practice, diversity is difficult to
assess quantitatively, and several diversity measures have been adopted:
alpha diversity is often estimated as the number of species in a
community (species richness), and beta diversity is often based on the
number of shared species among communities13.
Understanding the natural history of the microbiome over time is
important. Only then can we begin to understand how environmental
factors can impact the microbiome and subsequently how we can improve
the dysbiosis created. Kristensen et al.14 studied 20
infants with CF during the first 18 months of life and showed that
microbial development of the gut is different in healthy infants with CF
compared to healthy infants without CF. While all infants initially seem
to express a Bifidobacterium dominated profile, the microbiome in
CF infants further deviates over time. Bifidobacterium has been
shown to be associated with a range of beneficial health effects
including the regulation of intestinal microbial homeostasis, the
inhibition of pathogens and modulation of local and systemic immune
responses. Over time, environmental factor influence changes in the gut
microbiome including breastfeeding, exposure to transient bacteria
through daycare exposure/older siblings, and antibiotic exposure. In
this study, only infants with CF were observed to have significant
antibiotic exposure in the first 18 months of life. Stools were
collected monthly till 6 months of age and then at 8 , 10, 12, 15 and 18
months of age. Over time, infants with CF were more likely to be
colonized with pathogenic, proinflammatory bacteria such asStreptococci and Escherichia coli while control infants
were more likely to be colonized with healthy bacteria such asAkkermansia and Anaerostipes spp .
Microbial community alterations through natural history or based on
treatment/environmental factors contribute to CF pathophysiology.
Antibiotic use in infants with CF further worsens this dysbiosis leading
to a lower alpha diversity (decreased number of species), a further
reduced abundance of Bifidobacterium and Bacteroides and a
higher abundance of pathogenic bacteria, such as the Enterococcusgenus15. Khalaf et al. evaluated the role of acid
blockade in development of pulmonary infections, debunking the previous
presumption by showing that there is no influence of acid blockade on
the microbiome of the aerodigestive tract. They evaluated respiratory
(nasal and pulmonary) and gastrointestinal (oropharyngeal, esophageal,
gastric and duodenal) samples in 25 children with CF, on and off acid
blockade. There was no significant difference between alpha diversity,
beta diversity, total bacterial load and the presence of inflammation
(increased IL-8 levels) between those on acid blockade and those not on
acid blockage. In addition, there was no significant difference in
distribution between different anatomic locations, except for the nares.
The nares had a distinctly lower bacterial load, lower alpha diversity
and a different beta diversity. The authors conclude that acid blockade
does not play a significant role in the microbiome of the aerodigestive
tract.
Another important exposure that has been speculated to influence the gut
microbiome is secondhand smoke exposure (SHSe). Loman et
al.16 recruited a group of children with CF (as
defined by two-disease causing mutations and sweat chloride
>/= 60 mmol/L) ages 3 months to 5 years of age and analyzed
clinical questionnaire, nicotine content of hair,
oropharyngeal/respiratory samples, and fecal samples, noting xposure to
antibiotics within 1 month of collecti. Results showed that SHSe was
associated with an increase in Akkermansia, which is similarly
observed in primary smokers and healthy infants without CF.
Interestingly, Akkermansia is a mucin-degrading bacterium that is
important in maintaining the integrity of the gastrointestinal tract.
Decreased alpha diversity and a decrease in abundance of other
beneficial bacterium, Bifidobacterium and Lactobacillusspecies, was seen independent of SHSe, but potentially related to
antibiotic exposure. However, this causal relationship could not be
determined on the basis of this study due to the relatively small number
of participants. Loman et al. concluded that age, not exposure to SHSe
or antibiotics, was the predominant factor in determination of
microbiome composition in cohort of children with CF.
The alterations in the microbiome are starting to be linked to clinical
outcomes, especially in relation to growth. Analysis of the BONUS (Baby
Observational and Nutrition Study) identified an early, progressive
dysbiosis (decrease of Bacteroidetes and increase ofProteobacteria ) distinguishing CF infants with low length from
those with length17. Hayden et al. identified an early
progressive dysbiosis in infants with CF and low length compared to
infants with CF and normal length, including altered abundance of taxa
associated with functions important for nutrient harvest and growth
hormone signaling. They speculate that low length in infants with CF
correlates with lower serum levels of IGF (insulin-like growth
factors)-family of growth factors which may be modulated by the GI
microbiota through short chain fatty acid (SCFA) production. SCFA are
produced when gut microbiota ferment fiber and are known to induce IGF-1
which plays an important role in bone health and growth in infants and
children. Based on this speculation, manipulation of the gut microbiome
in infants with CF could potentially improve endocrine function
impacting growth, especially length.
Beyond the gut microbiome, the importance of the intestinal virome has
been more recently recognized. Coffey et al.18provided the first description of the intestinal virome in children with
CF comparing it to age matched control and finding differences in
taxonomy. In children with CF, Picornavirales ,Picornaviridae , and Enterovirus positively correlated with
weight and BMI, suggesting that the intestinal virome also contributes
to growth.
Alterations in the intestinal microbial and viral communities are one
marker of disease, however markers of inflammation are also important.
An indirect measure of inflammation in the gastrointestinal tract is
fecal calprotectin (FC), which is specific for neutrophils in the
mucosa. Beaufils et al.19 found that FC level
> 250µg/g was associated with worse gastrointestinal
symptoms and quality of life scores as measured by The Gastrointestinal
Symptoms Scales 3.0-PedsQLTM and the Quality-of-Life
Pediatric Inventory 4.0-PedsQLTM. It can be speculated
that in the future, a combination of fecal calprotectin, bacterial and
viral microbiome assessment will provide a complete picture of an
individual’s intestinal milieu.
LIVER
Understanding liver disease in CF is important as there can be serious
morbidity such as esophageal varices leading to hemorrhage and need for
liver transplantation. An improved understanding of the epidemiology,
various biomarkers, and novel testing modalities for liver disease in CF
have been published this year.
PUSH (Prospective Study of Ultrasound to Predict Hepatic Cirrhosis in
CF)20, a nine year, multicenter, case-controlled,
cohort study of children 3-12 years of age without known cirrhosis
reported interim findings after 4 years. Participants (n= 55) with
heterogeneous liver ultrasound were matched 1:2 to those with a normal
ultrasound pattern (n= 116). Biomarkers, GGT (gamma glutamyl
transferase), AST (aspartate transaminase), ALT (alanine transaminase),
platelets, AST to platelet ratio (APRI score) and Fibrosis Index based
on four factors (age, platelet count, AST and ALT) (FIB-4) were
significantly different at baseline in those with heterogeneous liver
ultrasound. Of those with a heterogeneous liver ultrasound, a relative
risk of 9.1 (95%CI 2.7 – 30.8) was seen in developing a nodular
ultrasound pattern in 13% (13/55) compared to 2.6 % (3/116) in those
with a normal pattern.
As briefly outlined above, the PUSH study evaluated various laboratory
markers, which other researchers have reported this year. Although the
studies have varied methods and findings, GGT has been shown to be a key
laboratory assessment. In a single center, retrospective, longitudinal
study, Karnsakul et al.21 evaluated the potential
predictivity for CFLD of numerous biomarkers: GGT alone, GGT to platelet
ratio (GPR), AST/ALT ratio, APRI score, FIB-4, and platelet count.
Cystic fibrosis liver disease (CFLD) was defined as objective evidence
of advanced liver disease or cirrhosis on imaging, biopsy or portal
hypertension (PH). All of the biomarkers were predictive of CFLD except
the FIB-4. GGT and GPR were noted to be representative of fibrosis, with
GGT viewed specifically as a marker of early disease. With the inclusion
of platelets alone or as part of GPR and APRI, a more sensitive
prediction of advanced liver disease evidence of PH can be made. For
example, patients with a GPR ≥ 0.28 had 141.9 increased odds of
developing CFLD. Further evaluation of biomarkers and their ability to
characterize PH was conducted in a cohort of 577 CF infants, diagnosed
by NBS at two Italian CF centers, followed longitudinally through age
18.5 years/201459. PH was diagnosed by the presence of
splenomegaly and confirmatory imaging. The overall incidence of PH was
8.8%, with those with PH having a 4 times higher mortality/transplant
risk. When analyzed as a whole to include all study sites or all
individuals at a single study site, elevations on two or more occasions
in GGT alone, as well as ALT alone, and combinations of elevations of
ALT/GGT, GGT/ALP and ALT/ALP were predictive of the later development of
PH. However as less than 30% of patients with PH had any of these
elevations, these parameters cannot be used on an individual patient
basis to predict disease progression. All of these studies have shown
the importance of GGT in predicting liver disease in CF either alone or
in coordination with other biomarkers, highlighting the importance of
obtaining a GGT when assessing liver enzymes.
Beyond biomarkers, there are many novel imaging modalities for CFLD that
have been reported on this year. Calvopina et al.22studied the potential of supersonic shear-wave elastography (SSWE)
assessment of liver stiffness measurements (LSM) at detecting CFLD
severity. CFLD was defined as the presence of at least two of three
signs or symptoms: hepatomegaly ± splenomegaly, persistent elevation (6
months) of ALT (1.5 × upper limit of normal ULN), or abnormal ultrasound
scan (showing abnormal echogenicity or nodularity suggesting
cirrhosis)23. Advanced CFLD was defined as CFLD with
PH evidence by the presence of splenomegaly on ultrasound. SSWE
determined LSM demonstrated good accuracy for detecting CLFD with LSM
being higher in those with CFLD (8.1 kPa, IQR 6.7-11.9) compared those
with CF but no liver diseases (6.2 kPa, IWR 5.6 – 7.0,
p<0.0001). Interestingly those with CF and no liver disease
were also able to be distinguished from healthy controls. In CF, a cut
off of 6.85 kPa had a sensitivity of 75% and a specificity of 71%,
with each 1 kPa increase in LSM associated with a 1.7-fold increase in
odds of having CFLD. Finally, they also found a cut off of 9.05 kPa was
able to discriminate mild from advanced liver disease. The studies on
CFLD in the past year have taken our understanding further which will
help with advances in treatment. By understanding the potential markers
of development of CFLD, caregivers can screen more effectively and
counsel patients about their potential CFLD risks.