Abstract
Patients with cystic fibrosis (CF) are at increased risk of malnutrition and growth failure due to multiple factors as a result of suboptimal or absent function of the CFTR chloride channel protein. Dysfunctional CFTR contributes to increased energy expenditure, exocrine pancreatic insufficiency causing impaired dietary macronutrient digestion and absorption, intestinal dysbiosis, and impaired bile acid homeostasis. Poor nutritional status as a result of these mechanisms is associated with decreased lung function, worse clinical outcomes, and ultimately, increased mortality. Nutritional interventions addressing these mechanisms, such as pancreatic enzyme-replacement therapy and enteral caloric supplementation, have improved nutritional status and, by association, clinical outcomes. In the last decade, the advent of medications targeting defective CFTR proteins has revolutionized the care of patients with CF by reducing the overall impact of CFTR dysfunction. Below, we summarize the effects of highly effective CFTR modulators on nutritional status overall as well as specific factors including bile acid metabolism, pancreatic function, energy expenditure, and intestinal dysbiosis. The future of CF nutrition care will require a paradigm shift away from focusing on methods addressing CFTR dysfunction such as excess calorie provision and toward an individualized, holistic approach in the context of specific mutations and CFTR-directed therapy.
Highlights
Patients with cystic fibrosis (CF) are at increased risk of malnutrition and growth failure due to multiple factors as a result of suboptimal or absent function of the CFTR chloride channel protein
In addition to impact on pulmonary function, CFTR modulator therapies impact growth and nutritional status to varying degrees, again with more robust effects seen with highly effective CFTR modulators as compared to dual combination therapies (LUM-IVA and TEZ-IVA) [6,9,13,14,15,16,17]
Multiple factors related to CFTR dysfunction have been associated with poor nutritional status in people with CF including increased pancreatic dysfunction in the form of exocrine pancreatic insufficiency (EPI or PI), CF-related diabetes, and impaired bicarbonate secretion; increased fatty acid turnover and energy expenditure; and factors associated with enteric homeostasis including bile salt loss in stool, increased inflammation, and small intestinal bacterial overgrowth [19]
Summary
The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein is an epithelial ion channel responsible for chloride transport across cell membranes. Mutations in CFTR are classified from I to VI based on their functional effects [1,2,3]. More than 2000 mutations have been found in the CFTR gene with variable effects on its function [4]. The most common CFTR mutation in the United States is the deletion of phenylalanine in position 508 (F508del), with 85% of individuals with CF possessing at least one copy of this mutation. While CFTR allele distributions vary highly among populations, no other mutation is currently found in more than five percent of individuals with CF in the United States. Based on data collected in the CF Patient registry, the two most common mutations are G542X, a class I mutation in which no functional CFTR is created, and G551D, a class III mutation, characterized by defective protein regulation or gating. G542X and G551D are present in 4.5 and 4.4 percent of people with CF, respectively [3,4,5]
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