Cystic fibrosis: Nutritional issues

INTRODUCTION — 

Historically, undernutrition and growth faltering were pervasive in people with cystic fibrosis (CF) and were associated with lung disease and reduced quality and length of life. Since the development and widespread use of highly effective modulator therapy (HEMT), undernutrition is less common and obesity and adverse cardiometabolic risk factors are increasingly seen.

The evaluation, monitoring, and treatment of nutritional problems will be addressed here. Related content can be found in the following topic reviews:

●Gastrointestinal and endocrine comorbidities

•(See "Cystic fibrosis: Assessment and management of pancreatic insufficiency".)

•(See "Cystic fibrosis: Overview of gastrointestinal disease".)

•(See "Cystic fibrosis: Hepatobiliary disease".)

•(See "Cystic fibrosis-related diabetes mellitus".)

●Other aspects of CF care

•(See "Cystic fibrosis: Clinical manifestations and diagnosis".)

•(See "Cystic fibrosis: Genetics and pathogenesis".)

•(See "Cystic fibrosis: Clinical manifestations of pulmonary disease".)

•(See "Cystic fibrosis: Overview of the treatment of lung disease".)

•(See "Cystic fibrosis: Management of pulmonary exacerbations".)

•(See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection".)

•(See "Cystic fibrosis: Management of advanced lung disease".)

•(See "Cystic fibrosis: Treatment with CFTR modulators".)

RELEVANCE OF CFTR MODULATOR THERAPY — 

Treatment with CF transmembrane conductance regulator (CFTR) modulators has dramatic effects on nutritional status, as well as benefits for CF lung disease and other manifestations. Highly effective modulator therapy (HEMT) refers to either elexacaftor-tezacaftor-ivacaftor, vanzacaftor-tezacaftor-deutivacaftor, or ivacaftor monotherapy, when used by those with at least one highly responsive CFTR gene mutation. Since the approval of elexacaftor-tezacaftor-ivacaftor in 2019, HEMT has been available to the vast majority of people with CF (PwCF) in the United States and other resource-abundant countries. (See "Cystic fibrosis: Treatment with CFTR modulators".)

Treatment with an effective CFTR modulator has important effects on nutritional outcomes and management:

●Those on HEMT – Many PwCF on HEMT achieve normal weight gain, and some have excessive weight gain or obesity [1]. These observations have led to modifications in the traditional high-fat, high-calorie diet for PwCF [2]. However, those who had advanced CF disease prior to starting HEMT are still at risk for malnutrition.

●Those not on HEMT – A small percentage of PwCF are not eligible for HEMT, because of their genotype and/or age, and others are unable to tolerate the available drugs. Furthermore, some people who are eligible are unable to access HEMT due to cost or other constraints. These individuals are at increased risk for nutrient deficits and warrant intensive management, including:

•Monitoring and prevention of micronutrient deficiencies, including of fat-soluble vitamins, fluoride, and zinc. (See 'Blood tests' below and 'Fat-soluble vitamins' below.)

•Monitoring for nutrition-related comorbidities, including bone disease, CF-related diabetes mellitus (CFRD), hepatobiliary involvement, small intestine bacterial overgrowth (SIBO), and pancreatitis. (See 'Nutrition-related comorbidities' below.)

•High-energy diet, which may include the traditional CF diet (now termed the "legacy diet") and/or oral or enteral nutrition support for selected PwCF. (See 'Nutrition support for undernourished people' below.)

PATHOPHYSIOLOGY

●Nutritional effects of CF – CF is caused by a defect in the CF transmembrane conductance regulator (CFTR), a cell membrane protein that forms a chloride channel and regulates chloride and water flux [3]. The spectrum of CF disease varies according to the genotype and with individual and environmental factors. The nutritional risks and requirements for an individual with CF also vary along this disease spectrum but do not precisely coincide with the severity of pulmonary disease.

Insufficient production and secretion of pancreatic enzymes (exocrine pancreatic insufficiency, often referred to simply as pancreatic insufficiency) causes malabsorption of fat; protein; and several micronutrients including the vitamins A, D, E, and K. Malabsorption of fat is exacerbated by bile salt abnormalities if there is concurrent intestinal or liver disease. Pancreatic function tends to decline with age. Across all age groups, most people with CF (PwCF) have marked pancreatic insufficiency. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency".)

Although pancreatic dysfunction is the major gastrointestinal contributor to malnutrition in CF, several other factors may contribute to the problem. These include CF hepatobiliary involvement (CFHBI), bile salt abnormalities, CF-related diabetes (CFRD), altered gastrointestinal motility, intestinal dysbiosis [4], and small bowel bacterial overgrowth (SIBO). Gastroesophageal reflux, distal intestinal obstructive syndrome, and constipation can also negatively affect nutrition. (See "Cystic fibrosis: Overview of gastrointestinal disease".)

In addition to malabsorption and gastrointestinal dysfunction, at least two other mechanisms contribute to nutritional deficiencies and growth failure in untreated PwCF: Chronic, progressive pulmonary infection with bronchiectasis leads to increased work of breathing and higher-than-expected nutrient needs [5], and chronic infection may reduce appetite and cause cytokine-induced catabolism [6]. In addition, chronic rhinosinusitis may impair the sense of smell, which can reduce appetite.

●Nutritional effects of highly effective modulator therapy (HEMT) – HEMT mitigates or normalizes CF-related nutritional deficits. As an example, ivacaftor improves weight gain in people with responsive mutations [7]. The mechanisms probably include restoring the normal, less acidic intestinal pH, as well as improving pancreatic function in young children (as measured by fecal elastase) but not in older individuals with established pancreatic insufficiency [7,8]. The long-term benefits of initiating HEMT in early childhood have not been established. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Pancreatic disease'.)

Other mechanisms through which HEMT improves nutritional outcomes include reducing energy expended in work of breathing [9]; reducing liver stiffness in CFHBI [10]; and reducing intestinal inflammation, which might improve nutrient absorption [11]. (See "Cystic fibrosis: Treatment with CFTR modulators", section on 'Efficacy'.)

ROUTINE ASSESSMENT AND MONITORING — 

Dietitians with special expertise in CF have a critical role in managing nutrition for people with CF (PwCF) and especially for those who are not on highly effective modulator therapy (HEMT). These services are available at CF centers in the United States.

Weight gain and growth

●Goals – Body mass index (BMI) is an important indicator of nutritional status range. The BMI goal depends, in part, on HEMT:

•Those not on HEMT – Target BMI above the 50^th percentile. This is the traditional target, established prior to the advent of HEMT, when PwCF rarely had excessive weight gain [12,13]. For children younger than two years of age, the same percentile criteria are applied to weight for length rather than BMI. For adults with CF, the target is a BMI at or above 22 for females and 23 for males [12,14]. To achieve these targets, dietary counseling emphasizes weight gain and high-energy foods (the "legacy diet"), although focusing on foods of high nutritional value is also important [2]. (See 'Oral' below.)

•Those on HEMT – Target BMI in the healthy range but generally avoiding the low end of the range. Thus, the optimal range for children is BMI between the 10^th and 85^th percentiles and the optimal range for adults is BMI 19 to 25 kg/m². Goals should be individualized, depending on coexisting CF disease manifestations, other comorbidities, and familial/genetic predisposition. Guidelines recommend an age-appropriate, healthy diet similar to that of the general population [14].

●Evidence – Historically, promoting weight gain was an important part of CF nutritional care because the nutritional status of individuals with CF tended to decline during childhood and weight gain was generally correlated with better outcomes. As an example, a study reported that young children who recovered from growth faltering within two years of their CF diagnosis had better pulmonary outcomes at age 12 years compared with children who continued to falter [15]. Similarly, a prospective, observational study using data from the CF Foundation (CFF) Registry showed that greater weight at age four years is associated with greater height, better pulmonary function, fewer complications of CF, and better survival through age 18 years [16].

However, advances in CF care have modified this perspective. Data from the CFF show that, on average, the BMI percentile for both children and adults has been increasing over the past 20 years, with additional increases after the widespread use of HEMT (figure 1) [17]. Indeed, HEMT is associated with increases in serum cholesterol, low-density lipoprotein cholesterol, and prevalence of obesity [18-20]. (See "Cystic fibrosis: Treatment with CFTR modulators", section on 'Other adverse effects'.)

●Monitoring – Careful and repeated nutritional assessments allow for early detection of nutritional deterioration. The CFF recommends that children with CF be seen every three months. A thorough dietary history and measurements of height and weight should be performed at each visit. Additional measures are tracked according to a schedule for nutrition assessment (table 1).

The practices for measuring growth in children with CF are the same as for healthy children. Each child's height, weight, and BMI should be tracked against standard curves provided by the United States Centers for Disease Control and Prevention. For children under two years of age, curves from the World Health Organization growth standards are used, recumbent length is tracked rather than height, and weight/length is used instead of BMI. (See "Measurement of growth in children", section on 'Recommended growth charts with calculators'.)

Another important indicator of nutritional sufficiency is the achievement of full genetic potential for height to identify possible growth delay or stunting. The genetic potential for height can be estimated by a variety of methods, one of which is the mid-parental target height prediction (calculator 1). This and other methods for calculating height potential are discussed separately. (See "Diagnostic approach to children and adolescents with short stature", section on 'Prediction of adult height'.)

●Interventions – Guidance to optimize nutrition should be provided to all PwCF. Those who do not meet target goals for BMI, whose linear growth is less than expected for their genetic potential, or whose growth rates begin to plateau require additional attention. These individuals should be given intensive counseling to optimize nutrition. They should also be further evaluated to identify reasons for nutritional deficits and potential contributors to malnutrition, including inadequate pancreatic enzyme replacement therapy, worsening lung disease, gastrointestinal disease, CF-related diabetes (CFRD) and CF hepatobiliary involvement (CFHBI), or causes unrelated to CF. (See 'Nutrition-related comorbidities' below.)

Conversely, those with excessive weight gain should be given counseling to encourage healthy diet and lifestyle habits, similar to other people with overweight or obesity. (See 'Management of overweight and obesity' below and "Prevention and management of childhood obesity in the primary care setting" and "Obesity in adults: Overview of management".)

In addition, assessment of psychosocial, economic, and behavioral factors that may contribute to suboptimal nutrition is essential. (See "Poor weight gain in children younger than two years in resource-abundant settings: Etiology and evaluation" and "Poor weight gain in children older than two years in resource-abundant settings".)

Blood tests — The CFF has developed a panel of recommended laboratory tests and testing intervals as part of the evaluation of nutritional status, as outlined in the table (table 2) [21,22]. Further details on laboratory tests related to nutritional status in the general population are available in a separate topic review. (See "Laboratory and radiologic evaluation of nutritional status in children".)

Nutrition-related comorbidities

Bone disease — Bone health is partly determined by nutritional factors in CF and is an important component of the nutritional assessment for all PwCF, regardless of treatment with CF transmembrane conductance regulator (CFTR) modulators.

●Epidemiology and risk factors – Bone disease, characterized by decreased mineral density, increased fracture rates, and kyphosis, is common in PwCF, even among those with pancreatic sufficiency [23,24]. Sixty percent of young adults have a kyphosis angle of >40°, contributing to height loss (mean 5.9 cm), chest wall deformities, and reduced lung volume and function [25]. Children and adolescents with CF also have higher-than-expected rates of fractures [26]. In a meta-analysis of studies of adults with CF (median age 28 years), the pooled prevalence of vertebral and nonvertebral fractures was 14 percent and 20 percent, respectively [27].

PwCF have multiple risk factors for developing bone disease [28]:

•Failure to thrive

•Delayed pubertal development

•Malabsorption of calcium, magnesium, vitamin D, and vitamin K due to fat malabsorption

•Hepatobiliary disease

•Reduced weightbearing activity

•Chronic corticosteroid use

•Inadequate intake of nutrients

The risk for bone disease increases with advancing age and severity of lung disease and malnutrition. As an example, the average bone density of adults with severe CF-related pulmonary disease is more than 2 standard deviations below the expected value and vertebral compression and other pathologic fractures are common [25].

●Screening – To monitor bone health, PwCF should have yearly determination of calcium, phosphorus, intact parathyroid hormone, and 25-hydroxyvitamin D levels (table 2) [24]. In addition, children should have an evaluation of bone density using dual-energy x-ray absorptiometry (DXA) starting at eight years of age, especially if risk factors are present (eg, BMI <10^th percentile for age, forced expiratory volume in one second <50 percent predicted, glucocorticoid use of ≥5 mg daily for ≥90 days/year, delayed puberty, history of fractures). Even when no risk factors are present, children should have a screening DXA scan by age 18.

DXA scanning is now widely available. Standards have been developed for the pediatric age group, and the findings are expressed as Z-scores to reflect age-specific standards (rather than T-scores, as in adults). However, interpretation remains problematic and requires adjustment for bone size and pubertal status; the unadjusted DXA Z-score for age and sex may systematically underestimate bone density in shorter individuals [29]. (See "Overview of dual-energy x-ray absorptiometry", section on 'Children'.)

In our practice, we take the following additional measures, depending on the results of the DXA scanning:

•If the DXA scan shows bone density within a healthy range (Z-score ≥-1), we repeat the DXA scan every two years in growing children. The interval can be increased to every five years for adults with initial results in a healthy range [24].

•If the DXA scan shows borderline bone mineral density (Z-score -1 to -2), additional measures are taken to diagnose and treat any endocrine contributors to the bone disease (CFRD, hypogonadism) and to minimize use of glucocorticoid medications. Additional low-impact weightbearing exercise is encouraged. Management includes supplemental calcium, phosphorus, and vitamin D (table 3 and table 4). DXA scans are repeated annually in growing children and every two to four years in adults.

•If the DXA scan shows markedly decreased bone mineral density (Z-score ≤-2), vitamin D, phosphorus, and calcium statuses are reviewed and vigorously replaced, in addition to each of the measures described above. DXA scans are repeated annually until they become normal.

●Prevention and treatment – All PwCF should be counseled to ensure that intake of the recommended amounts of calcium, phosphorus, vitamin K, and vitamin D is achieved to support bone health (table 3 and table 4). Weightbearing exercise should be encouraged, and low levels of vitamin D or vitamin K should be treated aggressively. Target levels for vitamin D (as 25-hydroxyvitamin D) are 30 to 60 ng/mL (75 to 150 nmol/L). (See 'Fat-soluble vitamins' below.)

Some groups have suggested that bisphosphonate treatment should be given to adults with CF who have markedly decreased bone mineral density (DXA Z-score <-2) [24]. In a systematic review that included 272 adults, oral and intravenous bisphosphonate treatment improved bone mineral density by approximately 5 percent at several sites after 12 months of therapy [30]. The analysis did not detect a significant difference in fracture rates between treated and untreated individuals. Intravenous administration of bisphosphonates was associated with severe bone pain and flu-like symptoms. Larger trials will be needed to determine if there are effects on fracture rates and survival.

Bisphosphonates should be approached with caution in growing children with CF. This is because osteopenia in growing children with CF may be due to decreased bone formation rather than increased reabsorption. Because bisphosphonates are essentially antiresorptive agents, giving them to growing children could lead to slow bone turnover. Moreover, there are increasing concerns about the use of bisphosphonates in children because these agents form bone with abnormal characteristics, they have extremely long half-lives, and the long-term risks and benefits have not been fully explored [31]. For these reasons, we do not use bisphosphonates for children or adolescents. Potential concerns for use of bisphosphonates in females who might later become pregnant are discussed separately. (See "Evaluation and treatment of premenopausal osteoporosis", section on 'Antiresorptive therapy with bisphosphonates'.)

Other nutrition-related comorbidities — Several other CF-associated comorbidities can cause or contribute to nutritional decline, including CFRD, pulmonary disease, and hepatobiliary disease. These issues are more likely to affect people with advanced CF and/or those who are not on CFTR modulator therapy. Key features to be considered in the nutritional evaluation are outlined below.

●CF-related diabetes mellitus (CFRD) – CFRD is a common cause of nutritional decline in PwCF and is also associated with declines in pulmonary function; treatment with insulin attenuates or reverses these effects. The prevalence of CFRD rises markedly with age so that CFRD affects approximately 15 percent of adolescents and almost 50 percent of adults over age 30 years. PwCF should be screened annually for CFRD using periodic oral glucose tolerance testing starting at 10 years of age. (See "Cystic fibrosis-related diabetes mellitus".)

●CF lung disease – There is a close correlation between pulmonary function test (PFT) results and nutritional status in PwCF (figure 2A-B) [15,32]. It is unclear whether worsening lung function causes nutritional deterioration (by decreasing intake or by increasing requirements) or whether deteriorating nutritional status causes poor performance on PFT testing (by weakening respiratory musculature or other mechanisms) [33-35]. In either case, the two are so closely linked that any child with worsening PFTs should be carefully evaluated for nutritional inadequacies. Declines in both pulmonary function and nutrition also may be symptoms of developing CFRD. (See "Cystic fibrosis: Overview of the treatment of lung disease".)

●CF hepatobiliary involvement (CFHBI) – CFHBI is a common and important complication of CF, occasionally leading to cirrhosis and portal hypertension and, very rarely, to liver failure [36]. Approximately 20 to 40 percent of PwCF develop clinically detectable CFHBI. Most of this CFHBI does not progress to severe disease, but, in the subset in which it does, it may progress rapidly. Individuals with CFHBI may have fat malabsorption because of insufficient or abnormal bile acids in the intestinal lumen, in addition to the underlying pancreatic insufficiency. Therefore, they require close attention to nutrition, including ensuring a high energy intake and adequate levels of fat-soluble vitamins. (See "Cystic fibrosis: Hepatobiliary disease".)

●Small intestine bacterial overgrowth (SIBO) – PwCF may be susceptible to SIBO because of decreased intestinal motility and dysbiosis. The disorder can contribute to malnutrition by decreasing appetite and by interfering with fat absorption. SIBO should be considered in PwCF with suggestive clinical symptoms and/or deterioration in nutritional status. There is evidence that HEMT reduces intestinal inflammation [11]. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Small intestine bacterial overgrowth'.)

●Pancreatitis – Pancreatitis develops in approximately 10 percent of PwCF with pancreatic sufficiency. Pancreatitis in PwCF typically presents during late adolescence or early adulthood. Acute pancreatitis is diagnosed by the combination of abdominal pain compatible with pancreatitis, serum amylase, and/or lipase values ≥3 times upper limits of normal as well as compatible imaging findings. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Pancreatitis'.)

●Intestinal resection – Approximately 10 percent of PwCF present as neonates with meconium ileus. Approximately one-half of these infants require surgical intervention, and some of those require resection of dilated, perforated, or atretic bowel, with diversion ileostomy. Resection of a significant portion of the distal ileum may lead to malabsorption of vitamin B12 and bile acids, which exacerbates malabsorption of fat and fat-soluble vitamins. Resection of significant portions of the small intestine can cause short bowel syndrome. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Meconium ileus' and "Management of short bowel syndrome in children".)

NUTRIENT GOALS

Calories — A wide range of energy requirements are reported in people with CF (PwCF), ranging from normal to 150 percent of normal, depending on the person's CF genotype; age; and current state of health, including CF lung disease, pancreatic disease, and CF hepatobiliary involvement (CFHBI).

In the past, the energy requirement for a person with CF was estimated to be 130 percent of recommended dietary allowance [37]. This is now considered an unwarranted simplification. A number of studies used open and closed indirect calorimetry and doubly labeled water to determine energy expenditures. These studies consistently show that energy expenditure is directly associated with the severity of the CF genotype and inversely associated with pancreatic function [38-40]. Accordingly, treatment with highly effective modulator therapy (HEMT) generally improves nutrition and weight gain [7].

Nutritional targets should be tailored to the individual's weight status and growth, disease severity, and receipt of HEMT [2,14,41]. Measurements of growth are the first and most important indicator of sufficient energy intake. If a child's body mass index (BMI) is in the target range (>10^th to 85^th percentile for age) and BMI and height are steadily increasing along a percentile curve, energy intake is likely sufficient (see 'Weight gain and growth' above). If the child's growth does not meet these targets, energy intake is probably suboptimal. In this case, it is reasonable to take action to empirically increase the child's energy intake (see 'Nutrition support for undernourished people' below). In addition, the child should be evaluated for possible causes of growth faltering, including insufficient pancreatic enzyme replacement therapy, gastrointestinal dysfunction, worsening pulmonary infection, or development of CF-related diabetes (CFRD). (See 'Nutrition-related comorbidities' above.)

Measurement of resting energy expenditure (indirect calorimetry) is not practical or needed for clinical management. The technique requires either endotracheal intubation or a tight-fitting hood to collect expired gases, and people with significant CF lung disease do not tolerate either method well.

Fat-soluble vitamins — CFHBI and pancreatic dysfunction lead to fat malabsorption, which predisposes to deficiencies of the fat-soluble vitamins: A, D, E, and K [42].

The CF Foundation (CFF) recommends supplementation of these fat-soluble vitamins for all PwCF (table 5 and table 4) [22]. These doses are considerably higher than those recommended for individuals without CF. Supplements should be started as soon as CF is diagnosed, including in asymptomatic infants and in individuals without pancreatic insufficiency. Several different commercially available vitamin supplements provide doses within the target range.

The effects of HEMT on fat-soluble vitamin status are unclear. A few reports describe modest increases in mean values for 25-hydroxyvitamin D and/or vitamin A after starting HEMT, with no effect on vitamin E [43,44]. However, cases of acute vitamin A toxicity have also been described, as outlined below [45-48]. Whether initiating HEMT in very young children might have a greater effect on fat-soluble vitamin levels is unknown. Until further information is available, guidance for supplementation and monitoring of fat-soluble vitamins is the same regardless of HEMT therapy. However, it is particularly important to be alert for vitamin A toxicity, monitor fat-soluble vitamin levels, and adjust doses as needed.

●Vitamin A – Because vitamin A is fat soluble and requires bile acids and lipase for absorption, people with CF-related hepatobiliary and pancreatic disease are at risk for vitamin A deficiency. However, except at the time of diagnosis, vitamin A deficiency is a rare occurrence in CF. Toxicity from vitamin A supplements is probably a more important clinical issue, as discussed below.

•Physiology – Vitamin A is important for vision, gene expression, reproduction, embryonic development, growth, and immune function. It exists as "preformed vitamin A" (retinol, retinal, retinoic acid, and retinyl ester) and as "provitamin A" (food composition data are available for alpha-carotene, beta-carotene, and cryptoxanthin; other forms of provitamin A for which no food composition data are available are also found in nature). Most supplements contain preformed vitamin A. (See "Overview of vitamin A".)

•Recommended intake – Supplementation with a water-miscible or water-soluble form of vitamin A has been a routine component of care for many years and is recommended by the CFF in the doses found in the table (1 mcg retinol activity equivalent = 3.33 international units vitamin A) (table 5).

•Toxicity – Several reports show that vitamin A may reach toxic levels in some PwCF who are taking supplements [49,50] and especially in those on HEMT [45-48]. Affected individuals may present acutely with symptoms and signs of intracranial hypertension including nausea, vertigo, blurry vision, and papilledema. Long-term vitamin A toxicity can cause bone mineral loss and liver abnormalities. Many of the supplements used for PwCF provide total doses of vitamin A that are well in excess of the CFF recommended intakes outlined above. The risk of toxicity is lower for certain supplements that supply part of the vitamin A in the form of beta-carotene (eg, DECAs brand). Beta-carotene is a provitamin A, and, because its conversion to vitamin A is physiologically regulated, it has a lower risk for toxicity compared with preformed vitamin A [42]. (See "Overview of vitamin A".)

•Monitoring – The CFF recommends measurement of serum retinol annually in all PwCF (table 2), as well as serum retinol-binding protein and retinyl esters for those with liver disease [21,42,51]. However, serum retinol is a better marker of deficiency than excess. The optimal forms and dosing of vitamin A supplements and approach to monitoring are subjects of active study. PwCF and their clinicians should also be alert for signs and symptoms of vitamin A toxicity, especially when starting HEMT or switching brands of fat-soluble vitamin supplements.

●Vitamin D – Vitamin D deficiency is common among PwCF and is probably a major contributor to bone disease [23,24]. (See 'Bone disease' above.)

•Physiology – Vitamin D3 (cholecalciferol) is the form in most over-the-counter supplements in the United States and is also the form produced in the skin by sunlight (figure 3). Vitamin D2 (ergocalciferol) is available by prescription and is in some over-the-counter supplements. Both forms are effective in increasing serum vitamin D levels, and it is unclear if one preparation is more efficacious than the other. The CFF recommends vitamin D3 (cholecalciferol) as an oral supplement because a small study suggests that it is somewhat more likely to achieve target 25-hydroxyvitamin D levels in PwCF compared with vitamin D2 (ergocalciferol) [52]. Vitamin D2 and vitamin D3 are hydroxylated in the liver to 25-hydroxyvitamin D (calcidiol), the major circulating form of the hormone. 25-hydroxyvitamin D is then converted in the kidney to the biologically active form of the vitamin, 1,25-dihydroxyvitamin D. In addition to its important role in bone health, vitamin D also has a role in muscle function, innate immunity, cardiovascular disease, and diabetes [53]. The metabolism and biologic roles of vitamin D are discussed in detail separately. (See "Overview of vitamin D".)

•Recommended intake – CF clinical practice guidelines recommend that all PwCF take vitamin D supplements: Recommended doses are 400 to 500 international units daily for children younger than one year of age and 800 to 1000 international units daily for those 1 to 10 years. After 10 years of age, the recommended daily intake is 800 to 2000 international units (table 4) [52].

There is some evidence that the dose of 800 international units daily that was previously recommended for children older than four years is not adequate; among children taking the recommended doses, at least 45 percent had vitamin D insufficiency (25-hydroxyvitamin D levels <30 ng/mL) [54]. Even with high-dose ergocalciferol treatment (50,000 international units three times weekly for eight weeks), vitamin D levels remained below the target range in 57 percent of participants. Similarly, a report from three Canadian CF centers documented that 95 percent of children with CF had suboptimal vitamin D status despite having daily vitamin D intake above 400 international units [23].

Strategies for repletion of vitamin D are discussed separately. (See "Vitamin D insufficiency and deficiency in children and adolescents", section on 'Treatment' and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

•Monitoring – Vitamin D status should be assessed annually in all PwCF by measuring serum 25-hydroxyvitamin D, preferably at the end of winter (table 2) [21,24]. Desirable levels are 30 to 60 ng/mL (75 to 150 nmol/L). If levels fall below 30 ng/mL, assure adherence to previously recommended supplements and supplement with vitamin D3 (cholecalciferol) (table 4) [24,52,54]. However, whether achieving 25-hydroxyvitamin D levels in the recommended target range (30 to 60 ng/mL) will cause clinically important improvements in bone health has not been established.

●Vitamin E – Because vitamin E functions as an antioxidant, some have proposed that vitamin E deficiency may promote inflammation and contribute to CF lung disease.

•Physiology – Vitamin E is a fat-soluble vitamin with eight different forms, each of which has its own profile of activity. All forms of vitamin E act as antioxidants at cell membranes, preventing membrane damage. The form most commonly used as a supplement is alpha-tocopherol acetate. Gamma-tocopherol may play an important and complementary role to alpha-tocopherol in scavenging free radicals [55]. (See "Overview of vitamin E".)

•Recommended intake – The CFF recommends intake of vitamin E (as alpha-tocopherol), as shown in the table (table 5) [21]. These doses are approximately 20-fold higher than the recommended intake for healthy individuals and are generally effective in preventing vitamin E deficiency (as measured by alpha-tocopherol levels) [56].

The known role of vitamin E as an antioxidant has generated interest in the possibility that higher doses of vitamin E, or different forms of vitamin E alone or in combination with other antioxidants, might reduce inflammation and end-organ damage in CF. This hypothesis is supported by some studies showing a correlation between vitamin E status, polyunsaturated fatty acid status, and inflammation in PwCF [56]. However, clinical efficacy for this approach has not been established and supplements in excess of the above dosing ranges are not generally recommended.

•Monitoring – The CFF recommends annual measurements of serum alpha-tocopherol to monitor vitamin E status in PwCF (table 2) [21]. Serum vitamin E levels are strongly influenced by the concentration of serum lipids, and PwCF tend to have lower serum cholesterol levels than those of the reference population. Hence, serum vitamin E levels alone may not accurately reflect tissue vitamin levels and the alpha-tocopherol:cholesterol ratio or alpha-tocopherol:total serum lipid ratio may be a better measure of sufficiency.

●Vitamin K – Vitamin K deficiency can cause coagulation abnormalities and may also contribute to bone disease in PwCF. Several reports demonstrate a direct correlation between vitamin K status and measures of bone health [42,57-59]. (See 'Bone disease' above.)

•Physiology – Vitamin K is a fat-soluble vitamin found in a variety of green vegetables and is also synthesized by intestinal bacteria. PwCF are at risk for vitamin K deficiency because of fat malabsorption and also because of disturbances in the bowel flora associated with small intestine bacterial overgrowth (SIBO) or frequent use of antibiotics.

Vitamin K is a cofactor required for the activity of several key proteins in the coagulation pathways, including prothrombin. Because vitamin K-dependent carboxylation occurs in the liver, its action can be further reduced in PwCF who have severely impaired hepatic function. Vitamin K-dependent carboxylation is also necessary for function of osteocalcin and other bone-related proteins. (See "Overview of vitamin K".)

•Recommended intake – The CFF recommends vitamin K supplementation of 0.3 to 0.5 mg daily for infants, children, and adolescents with CF [21]. Adults should be supplemented with 2.5 to 5 mg weekly, and additional supplementation may be necessary during antibiotic therapy (table 5) [51]. These doses are over 100-fold higher than the recommended intake for individuals without CF.

•Monitoring – The CFF recommends annual screening for vitamin K deficiency in individuals with liver disease, hemoptysis, or hematemesis; screening consists of measuring serum prothrombin time and, if possible, PIVKA-II (proteins induced by vitamin K absence) levels (table 2). In our practice, we perform these screening tests annually in all PwCF even if there is no known liver disease or bleeding diathesis, because some may have CFLD for some time before it becomes clinically apparent.

PIVKA-II is more sensitive compared with prothrombin time in detecting vitamin K deficiency. Using this measure, 40 percent of PwCF were found to have suboptimal vitamin K status, despite meeting the goals for vitamin K intake recommended by the CFF [60].

Essential fatty acids — PwCF often have an abnormal fatty acid profile, with relatively low levels of essential fatty acids (EFAs), but clinically apparent EFA deficiency is rare. Monitoring is suggested for those with risk factors [61,62].

●Physiology – EFAs are termed "essential" because they cannot be synthesized by humans; they can be categorized as:

•Omega-3 fatty acids – Including alpha-linolenic acid and docosahexaenoic acid. These are found in high concentrations in fish oil and are relatively high in the Mediterranean diet. They exhibit profound antiinflammatory effects, raising the possibility that they could be beneficial in chronic inflammatory states including CF. Clinical trials of fish oil have found some clinical benefits in rheumatoid arthritis. (See "Nonpharmacologic therapies for patients with rheumatoid arthritis", section on 'Nutrition and dietary therapy'.)

•Omega-6 fatty acids – Including linoleic acid and its active metabolite, arachidonic acid, which have proinflammatory effects but are also important markers of nutritional status in children with CF [63].

●Clinical manifestations – EFA deficiency is characterized by scaly dermatitis, alopecia, thrombocytopenia, and growth failure. Overt symptoms of EFA deficiency such as these are uncommon in PwCF, but there is some evidence for subclinical EFA deficiency in this population. As an example, biochemical markers of EFA deficiency are correlated with poor growth and pulmonary status [63,64]. EFA deficiency is more common among infants and individuals with pancreatic insufficiency.

●Monitoring – Routine EFA monitoring is not recommended for PwCF [21,22]. However, those at high risk for EFA deficiency, such as infants with growth faltering or other suggestive symptoms or malnourished individuals, should be monitored periodically (table 2) [65].

The preferred method for assessing fatty acid status is to measure the total fatty acid profile in red blood cells. EFA deficiency is likely when the levels of linoleic, alpha-linolenic, and eicosapentaenoic acids and docosahexaenoic acid are below reference range. This test has the advantage of providing information on omega-3 as well as omega-6 fatty acids but is not widely available [65,66].

If this test is not available, EFA status can be partially evaluated by measuring the triene:tetraene ratio in blood; a ratio >0.2 suggests EFA deficiency. This is the traditional approach for assessing EFA deficiency, but its validity has been questioned because it only provides information about omega-6 fatty acids [67].

●Supplementation – For all PwCF, diets rich in EFA, including cold-water fish and vegetable oils (eg, flax, canola, soy), are encouraged [21].

Routine supplementation with EFAs is not recommended, because clinical benefits have not been demonstrated [61,62]. A systematic review found that short-term supplementation with omega-3 fatty acids improved several indices of CF lung disease and concluded that the supplements may be beneficial and have few adverse effects [61]. However, this was based on five small studies with low quality of evidence and more evidence is required before supplementation of EFAs can be routinely recommended for PwCF.

Supplementation and dietary modification are required for individuals with documented EFA deficiency.

Sodium supplementation — PwCF are prone to hyponatremic dehydration under conditions of heat stress, especially with exercise. This was described in five children who developed heat exhaustion with low serum sodium during a summer heat wave in 1948 [68]. The risk for hyponatremic dehydration is increased during infancy and in hot climates [69]. A similar picture can develop in infants without heat stress [70]. To avoid these potentially life-threatening complications, routine supplementation with sodium chloride is recommended, depending on the individual's age and climate conditions (table 6) [22]. Supplementation is particularly important for infants because of higher insensible losses due to their high surface-to-volume area and relatively low salt intake in a typical infant diet.

For people taking HEMT, the need for salt supplementation appears to be reduced. Nonetheless, until more definitive information is available, we suggest using the same supplementation protocols for people on HEMT, and particularly for infants, or for older children and adults engaging in prolonged exercise and/or in hot environmental conditions. Monitoring of blood pressure, particularly in older children and adults, is needed [2].

Other minerals

●Fluoride – Infants and children with CF require fluoride for dental health at the same levels as healthy children [22]. Vitamins formulated for CF do not generally include fluoride. Fluoride supplements should be supplied separately beginning at six months of age, if the fluoride concentration of the water supply is not adequate. (See "Preventive dental care and counseling for infants and young children", section on 'Fluoride'.)

●Zinc – For infants with CF under two years of age who are not growing well despite adequate energy intake and pancreatic enzyme supplementation, the CFF suggests an empiric trial of zinc supplementation (1 mg elemental zinc/kg/day in divided doses for six months) [21]. An empiric trial is used because there is no good laboratory test to determine zinc deficiency. This suggestion is based on expert consensus, inferred from the positive effects of zinc on growth in some other clinical settings. (See "Zinc deficiency and supplementation in children", section on 'Enhancement of growth'.)

Rarely, infants with undiagnosed CF may present with a dermatitis caused by zinc deficiency, often in combination with EFA deficiency and/or protein-energy malnutrition. The dermatitis resembles acrodermatitis enteropathica. (See "Zinc deficiency and supplementation in children", section on 'Underlying medical conditions'.)

NUTRITION SUPPORT FOR UNDERNOURISHED PEOPLE

Oral — People with CF (PwCF) who are underweight, and especially children with poor weight gain, should have interventions to promote weight gain. This includes dietary and behavioral interventions designed to boost caloric intake above that for the general population. Dietary guidance typically emphasizes foods with relatively high fat and caloric content to promote weight gain (sometimes described as the "legacy diet" because it reflects guidance prior to the advent of highly effective modulator therapy [HEMT]). Dietary guidance also encourages foods with high nutritional value as part of this high-calorie diet, but implementation can be challenging [71]. Pancreatic enzyme replacement therapy should be provided for those with pancreatic insufficiency. (See 'Weight gain and growth' above and 'Calories' above and "Cystic fibrosis: Assessment and management of pancreatic insufficiency".)

●Infants – For infants with CF, human milk feeding is specifically encouraged [22]. If infants are fed formula, a standard infant formula may be used; formulas containing extensively hydrolyzed protein are not helpful, unless the infant has a formula protein intolerance in addition to CF. If weight gain is inadequate, the energy content of the formula or human milk should be increased using standard methods. (See "Poor weight gain in children younger than two years in resource-abundant settings: Management", section on 'Strategies to increase intake'.)

●Behavioral support – Parents and caregivers should be educated to use behavioral techniques to promote positive feeding behaviors [22]. These include:

•Providing attention and praise for positive eating behaviors

•Gentle persistence when offering new foods (offer a new food 10 or more times before giving up)

•Ignoring negative eating behaviors such as food refusal

•Offer meals and substantive snacks on a regular schedule

•Keep mealtimes relaxed and time limited; do not enforce specific goals for intake at each meal

●Methods to promote caloric intake – For children with suboptimal growth, the initial intervention is to provide more intensive dietary advice to increase caloric intake [13,22]. A number of studies support this approach and show nutritional benefit through counseling with the use of behavior modification strategies to support dietary change [72-76]. As an example, a small randomized trial found that a behavioral intervention substantially increased caloric intake in toddlers and preschool-aged children with CF as compared with standard care and that these effects persisted 12 months after the intervention [77,78]. The behavioral techniques included differential attention (parents praised children for desired eating behaviors and ignored noneating behaviors) and contingencies (rewards to motivate children to meet energy goals). A larger multicenter trial of children aged 4 to 12 years assessed the efficacy of a similar behavioral intervention designed to promote energy intake [79,80]. The group receiving the behavioral intervention achieved improved energy intake and weight gain at the end of a nine-week intervention and a slower rate of decline in body mass index (BMI) Z-score over the subsequent two years as compared with control participants who received nutritional education alone.

●Management of pancreatic insufficiency – In addition to nutritional and behavioral counseling, individuals with suboptimal growth should also be assessed for the possibility of emerging pancreatic insufficiency or inadequate replacement therapy; for older children and adolescents, a decline in nutritional status may be a symptom of emerging CF-related diabetes (CFRD). In addition, other types of gastrointestinal disease such as celiac disease or inflammatory bowel disease should be considered. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency" and "Cystic fibrosis-related diabetes mellitus".)

●Other interventions – For infants with CF under two years of age who are not growing well despite adequate energy intake and pancreatic enzyme supplementation, the CF Foundation (CFF) suggests a trial of zinc supplementation. (See 'Other minerals' above.)

If dietary counseling is not successful, a liquid supplement that is high in calories and protein can be added to the diet [13]. A variety of commercial liquid supplements are available and are appropriate for use by PwCF. These generally provide appropriate macronutrient balance; the choice depends primarily on palatability, cost, and availability. These supplements are often less efficacious than expected because the supplements tend to displace ordinary food rather than being taken in addition to a usual diet [81] and some individuals complain of taste fatigue with oral supplements. As an example, a systematic review found that calorie-protein supplements do not confer benefits above dietary advice and monitoring in PwF who have moderate malnutrition [82].

Pharmacologic options

●Appetite stimulants – There is inadequate evidence to recommend any appetite stimulant. A number of appetite stimulants have been tried in attempts to reverse a downward trend in growth for children with CF. Medications that have been tried include megestrol acetate, cyproheptadine, dronabinol (a cannabinoid), and mirtazapine (an antidepressant) [83]. There have been concerns about the efficacy, length of treatment, and side effects with all of these drugs. There is some evidence that megestrol acetate can cause short-term weight gain, including lean body mass, and can result in improved lung function [84-86]. Since it is a steroid, it can have steroid-like side effects. Adrenal suppression and testicular failure have been reported. Long-term use has not been fully evaluated. Cyproheptadine generally leads to short-term improvement in appetite and is primarily useful to overcome an acute and temporary anorexia; it has antihistamine-like side effects. The long-term efficacy of cyproheptadine is less well established [87].

●Insulin – In individuals with CFRD (with or without fasting hyperglycemia), treatment with insulin has beneficial effects on nutrition and probably also on pulmonary function. The benefits of insulin therapy are less well established for individuals with earlier stages of CF-related dysglycemia. The possibility of CFRD should be considered in PwCF with progressively worsening nutritional status. (See "Cystic fibrosis-related diabetes mellitus", section on 'Indications'.)

●Growth hormone – Data are insufficient to justify routine use of growth hormone in this population outside of a clinical study. A few clinical trials have examined the use of recombinant growth hormone in children with CF and growth failure, with 12 months of follow-up [88,89]. These have shown modest improvement in height, weight, and lean tissue mass compared with no treatment and a very small improvement in forced vital capacity but not other measures of pulmonary function [90]. No adverse effects on blood glucose were noted.

Enteral feedings — When oral nutrition support fails to yield adequate weight gain (as indicated by progressively decreasing BMI percentiles), enteral nutrition (tube feeding) should be employed [12,13,91]. Aspects of enteral nutrition that are specific to PwCF are outlined here. An overview of enteral nutrition in children is presented separately. (See "Overview of enteral nutrition in infants and children".)

●Evidence – Enteral nutrition is widely used for PwCF who are malnourished and is perceived to be helpful [92-94]. This practice is supported by a number of observational studies that suggest improved nutritional status and stabilization of lung function in PwCF receiving enteral nutrition [93,95,96]. No randomized studies of enteral nutrition have been performed in PwCF. Therefore, the clinical benefits and potential adverse consequences, including effects on quality of life, have not been rigorously addressed [96].

●Route – Enteral nutrition is usually provided to PwCF via gastrostomy tube because nasogastric tubes are usually poorly tolerated due to chronic cough, nasal polyps, and the sensation of suffocating. Gastrojejunostomy and jejunostomy feeding may also be used, but these tubes are more difficult to place and maintain in position. Additionally, jejunal feeds must be given continuously rather than in boluses, making the route inconvenient for ambulatory individuals. Gastrostomy tubes can be placed surgically, endoscopically, or by an interventional radiologist, with minimal risk. If general anesthesia is not advisable, the procedure can be performed under sedation and local anesthesia. A skin-level device (or "button") can be used so that the individual can disconnect from all tubing between feeds to optimize mobility and cosmesis.

●Schedule – Schedules for tube feeding vary and should take into account the individual's activities and other therapies. Feeds can be instilled continuously, as boluses, or as a combination of these two regimens.

For the school-aged child, a frequently employed schedule supplies approximately 40 percent of daily requirements via a slow infusion overnight and the remainder of the requirement is supplied through food taken by mouth during the day. If the child is unable to meet the daily energy requirements, the nighttime infusions can be lengthened or the rate of infusion increased so that a greater percentage of the requirements are delivered overnight.

For the younger child who is at home during the day, nutritional requirements can be supplied through a combination of nighttime continuous feeds, daytime meals, and daytime bolus feeds. If the child fails to ingest the prescribed amount at any daytime meal, a bolus feed is added to compensate.

PwCF often have a complex care schedule because of their need for multiple medications and frequent pulmonary therapies. Feeding schedules should take these other elements of therapy into account.

●Formula – No one class of formula has been shown to be superior to another. Some formulas supply protein that is either elemental (free amino acids) or semielemental. The protein in a semielemental formula may be extensively hydrolyzed (containing short peptides) or partially hydrolyzed (containing longer peptide chains). However, more extensive protein digestion does not have a clinical advantage as long as pancreatic enzyme replacement is given and it may have the disadvantage of increasing the osmolarity of the formula. In one study, standard (intact protein) formula plus pancreatic enzyme replacement was as well absorbed as a semielemental formula without pancreatic enzymes [97]. (See "Overview of enteral nutrition in infants and children", section on 'Formula selection'.)

Concentrated formulas with 1.5 to 2 kcal/mL have the advantage of delivering more calories in a smaller volume. Since nighttime urination is a problem when using high-volume overnight feeds, a smaller volume can make the feeding schedule more tolerable. When using the more concentrated formulas, care must be exercised to avoid carbohydrate overload and possible inadequate supply of free water. Use of formulas with concentrated carbohydrates may uncover CFRD. Similarly, for people with established CFRD, these formulas may complicate diabetes treatment. The complications encountered because of CFRD are surmountable and should not preclude the use of enteral nutrition.

Several types of formulas consisting of blenderized foods are also available. Although some are nutritionally complete formulas, they offer no nutritional advantage over the traditionally used enteral formulas.

●Pancreatic enzymes for enteral feeds – There is little evidence to determine the best way to administer pancreatic enzyme replacement therapy in conjunction with enteral nutrition. We suggest the following approach:

•Start by calculating the grams of long-chain triglycerides (LCT) being administered. LCT is the main determinant of the lipase requirement because medium-chain triglycerides (MCT) require relatively low concentrations of lipase to hydrolyze the fatty acids from the glycerol backbone. Therefore, MCT accounts for little of the fat malabsorption in CF. The LCT:MCT content varies among formulas.

•Supply 1600 to 2000 lipase units/gram LCT; refer to pancrelipase drug information. Methods for administering pancrelipase coated in microspheres and avoiding blockage are described in a study [98].

-For cycled and continuous overnight feeds, administer three-fourths of the enzymes at the beginning of the feeding and one-fourth of the enzymes at the end of the feeding.

-For bolus feedings, administer the calculated amount of enzymes just prior to the feeding.

-For continuous 24-hour feedings, divide the total calculated lipase into six doses and give each dose at four-hour intervals.

Alternatively, lipase can be supplied by a cartridge delivery system (Relizorb) that is placed in line with the feeding tube. This system has been approved by the US Food and Drug Administration for use in children two years of age and older. Efficacy data are still limited, but a small trial suggests that the system can help reduce early morning satiety and bloating for some individuals [99]. An open-label observational study showed steady improvements in height and weight Z-scores during 12 months of treatment but was limited by lack of a comparison group [100]. This approach cannot be used with formula containing insoluble fiber. Unlike the oral pancreatic enzyme replacement products, the lipase within the cartridge is not a porcine extract and does not include amylases or proteases. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency", section on 'Dosing considerations'.)

(See "Cystic fibrosis: Assessment and management of pancreatic insufficiency", section on 'Pancreatic enzyme replacement therapy'.)

Parenteral nutrition — Parenteral nutrition (PN) should be prescribed for PwCF when gastrointestinal function is inadequate to supply complete nutrition. This could occur during times of extreme metabolic stress, such as recovery from gastrointestinal surgery or transplantation procedure. The PN solution should contain a balance of amino acids, dextrose, lipids, vitamins, and trace elements to provide appropriate nutrition. (See "Parenteral nutrition in infants and children", section on 'How to prescribe parenteral nutrition'.)

One study observed that PN promoted weight gain in undernourished PwCF but was also associated with higher rates of sepsis [101]. Moreover, after PN was discontinued, weight decreased again and no long-term gain was achieved. PN should not be a part of palliative care.

MANAGEMENT OF OVERWEIGHT AND OBESITY — 

Overweight, obesity, and associated adverse cardiovascular risk factors are increasingly common among people with CF (PwCF) due to advances in CF care, particularly highly effective modulator therapy (HEMT), as well as societal trends. (See 'Weight gain and growth' above and "Cystic fibrosis: Treatment with CFTR modulators", section on 'Other adverse effects'.)

Very limited evidence is available regarding optimal management of overweight and obesity in PwCF. Current guidance suggests weight management approaches similar to those of the general population, including an age-appropriate, healthy, balanced diet, emphasizing vegetables, fruits, whole grains, seafood, and lean proteins, coupled with physical activity and behavioral support [14]. Recommendations for macronutrient distribution and fiber intake are also the same as for the general population. Children with class II or greater obesity may benefit from a clinician with special training in weight management. (See "Prevention and management of childhood obesity in the primary care setting" and "Obesity in adults: Overview of management".)

Fat-soluble vitamin supplementation is generally recommended regardless of weight status, with periodic laboratory monitoring to ensure appropriate dosing. (See 'Fat-soluble vitamins' above.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cystic fibrosis".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Cystic fibrosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical importance – Historically, undernutrition and growth faltering were pervasive in people with cystic fibrosis (PwCF) and were associated with lung disease and reduced quality and length of life. Since the development and widespread use of highly effective modulator therapy (HEMT), undernutrition is less common and obesity and adverse cardiometabolic risk factors are increasingly seen. A small percentage of PwCF are not able to access HEMT, because of their genotype and/or age, cost, or other constraints. Thus, nutrition management requires close monitoring and individualized care to support healthy growth and body weight. (See 'Relevance of CFTR modulator therapy' above.)

●Causes of nutritional problems in CF – Pancreatic dysfunction is the major gastrointestinal contributor to malnutrition in CF, which causes fat malabsorption, fat-soluble vitamin deficiencies, and bone disease. Other factors include CF hepatobiliary involvement (CFHBI), bile salt abnormalities, altered gastrointestinal motility, and small intestine bacterial overgrowth (SIBO). In people with advanced disease, the lung disease increases nutritional needs and CF-related diabetes mellitus (CFRD) is common and an important cause of nutritional decline. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency" and "Cystic fibrosis-related diabetes mellitus".)

●Routine monitoring

•Anthropometrics – Children with CF should have regular nutritional assessments to monitor and optimize nutrition (table 1). Close monitoring is particularly important for those who are not on HEMT. (See 'Routine assessment and monitoring' above.)

•Body mass index (BMI) targets – For people who are not on HEMT, the traditional BMI targets are above the 50^th percentile for children (figure 1) and at or above 22 kg/m² for adult females and 23 kg/m² for adult males. For people on HEMT, the target BMI is in the healthy range but generally avoiding the low end of the range. Thus, the optimal range for children is BMI between the 10^th and 85^th percentiles and the optimal range for adults is BMI 19 to 25 kg/m². Goals should be individualized, depending on coexisting CF disease manifestations, other comorbidities, and familial/genetic predisposition. (See 'Weight gain and growth' above.)

•Blood tests – Laboratory tests are performed to monitor for micronutrient deficiencies (table 2). (See 'Blood tests' above.)

●Management of nutritional comorbidities

•Bone health – Bone disease is common in PwCF and progresses with age. All PwCF should be counseled to ensure recommended intake of calcium, phosphorus, vitamin K, and vitamin D to support bone health (table 3 and table 4). In addition, serum levels of calcium, phosphorus, intact parathyroid hormone, and 25-hydroxyvitamin D should be measured annually; bone density should be measured in children older than eight years (table 2). (See 'Bone disease' above.)

•Fat-soluble vitamin malabsorption – For all PwCF, we suggest providing a fat-soluble vitamin supplement designed to meet CF-specific recommended intakes (table 5 and table 4) (Grade 2C). Several different commercially available vitamin supplements provide doses within the target range. Fat-soluble vitamin status should be assessed with annual laboratory monitoring and doses adjusted if needed (table 2). Care should be taken to monitor for signs and symptoms of vitamin A toxicity, especially when HEMT is started, because case reports describe hypervitaminosis A in people on HEMT. (See 'Fat-soluble vitamins' above.)

•Sodium requirements – PwCF, and particularly infants, are prone to hyponatremic dehydration under conditions of heat stress because of sodium losses in sweat. Most children with CF will need supplementation of sodium chloride to compensate for estimated sodium losses, which depend on the individual's age, climate conditions, strenuous exercise, and, possibly, HEMT (table 6). (See 'Sodium supplementation' above.)

●Diet and nutrition support – All PwCF should be given dietary counseling to encourage a balanced diet with adequate calories to ensure good growth. For those who are undernourished, caloric goals are typically higher than those of the general population. Those with growth failure can be managed with a series of interventions, beginning with intensive counseling and escalating to nutritional supplements via the oral or enteral route. Parenteral nutrition (PN) has a limited role in the management of CF. (See 'Nutrition support for undernourished people' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Chris Coburn-Miller, MSRD, CSP, and Robert D Baker, MD, PhD, who contributed to earlier versions of this topic review.