Version January 2024
INTRODUCTION — Children and adolescents with cystic fibrosis (CF) frequently have growth failure caused by the combination of malabsorption, increased energy needs, and reduced appetite. Nutrient delivery and correction of maldigestion and malabsorption are essential to achieve normal growth to support optimal pulmonary function and prolong life.
The CF Foundation (CFF) patient registry has documented substantial improvement in life expectancy of patients with CF (figure 1) [1]. To a large degree, the longer life achieved by patients with CF can be ascribed to improved treatment of lung disease, pulmonary toilet, potent and tailored antibiotics, dornase alfa (DNase), lung transplantation, and early diagnosis via newborn screening. However, greater emphasis on CF nutrition is considered important to improve longevity and quality of life. As a result, the CFF created a consensus report on practical aspects of nutrition in pediatric CF [2] and a more theoretic report on gastrointestinal outcomes and confounders in CF [3].
The advent of CF transmembrane conductance regulator (CFTR) modulators has substantially changed the outlook for patients with CF lung disease (see "Cystic fibrosis: Treatment with CFTR modulators"). Modulator therapy has also altered growth and nutrition statistics. It is likely that they will have an effect on growth and nutrition, but the full impact of these potent drugs is yet to be determined [4]. While there is no doubt that these drugs will change the need for nutritional interventions, the discussion below remains valid.
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".)
PATHOPHYSIOLOGY — CF is caused by a defect in the CF transmembrane conductance regulator (CFTR), a cell membrane protein that forms a chloride channel and that regulates chloride and water flux [5]. The spectrum of CF disease varies according to the genotype and with individual and environmental factors. The nutritional risks and requirements for a patient with CF also vary along this disease spectrum but do not precisely coincide with the severity of pulmonary disease.
Insufficient production 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, approximately 90 percent of patients with CF 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-related liver disease (CFLD), bile salt abnormalities, CF-related diabetes mellitus, altered gastrointestinal motility, intestinal dysbiosis [6], and small bowel bacterial overgrowth. 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, two other mechanisms contribute to nutritional deficiencies and growth failure in patients with CF: chronic, progressive pulmonary infection with bronchiectasis leads to increased work of breathing and higher than expected nutrient needs [7], and chronic infection may reduce appetite and cause cytokine-induced catabolism [8].
PANCREATIC INSUFFICIENCY — Pancreatic insufficiency is a major contributor to nutritional problems in patients with CF. The diagnosis and management of pancreatic insufficiency in this population, including strategies for pancreatic enzyme replacement, are discussed separately. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency".)
The nutritional problems that may be caused by pancreatic insufficiency, including growth failure, fat-soluble vitamin deficiencies, and bone disease, are addressed below.
ASSESSING AND MONITORING NUTRITION — The most effective way to maintain good nutritional status in CF, as in other chronic diseases, is to prevent suboptimal nutrition from occurring.
Growth
●Goals – An important indicator of adequate nutritional status is body mass index (BMI) in a healthy range. For children with CF, the BMI target range is above the 50th percentile [9,10]. Children with BMIs between the 10th and 50th percentiles are generally considered at nutritional risk, and those with BMIs below the 10th percentile are in need of nutritional rehabilitation. 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 [9].
The nutritional status of individuals with CF tends to decline during childhood. However, data from the CF Foundation (CFF) show that, on average, the BMI percentile for both children and adults has been increasing over the past 20 years (figure 2) [1]. A prospective, observational study using data from the 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 [11]. Treatment with CF transmembrane conductance regulator (CFTR) modulators may further improve weight gain and nutritional status, but the full impact of these drugs is yet to be determined [4]. Some CF patients are overweight (BMI >85th percentile) and even obese (BMI >95th percentile), and this may become more of an issue in the era of CFTR modulator therapy [12].
●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 patient'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 (WHO) 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; an approach that only emphasizes BMI may overlook children with 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 individuals with CF. 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 patients 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 and small bowel bacterial overgrowth (see 'Pathophysiology' above). In addition, assessment of psychosocial, economic, and behavioral factors that may contribute to suboptimal nutrition is essential.
As soon as a decline in growth parameters is documented, nutritional intervention should begin (see 'Nutrition support' below). In addition, patients should be evaluated for comorbidities that may explain the nutritional decline, including worsening lung disease, CF-related diabetes (CFRD) and CF-related liver disease (CFLD). (See 'Evaluation for comorbidities' below.)
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) [2,13].
Evaluation for comorbidities — Bone health is partly determined by nutritional factors in CF and is an important component of the nutritional assessment. Conversely, several other CF-associated comorbidities can cause or contribute to nutritional decline, including CFRD, pulmonary disease, and hepatobiliary disease. Key features to be considered in the nutritional evaluation are discussed below.
Bone disease
●Epidemiology and risk factors – Bone disease, characterized by decreased mineral density, increased fracture rates, and kyphosis, is common in patients with CF, even among those with pancreatic sufficiency [14,15]. Sixty percent of young adults have a kyphosis angle of >40 degrees, contributing to height loss (mean 5.9 cm), chest wall deformities, and reduced lung volume and function [16]. Children and adolescents with CF also have higher than expected rates of fractures [17]. In a meta-analysis of studies of adults with CF (median age 28 years), the pooled prevalence of vertebral and non-vertebral fractures was 14 percent and 20 percent, respectively [18].
Individuals with CF have multiple risk factors for developing bone disease [19]:
•Failure to thrive
•Delayed pubertal development
•Malabsorption of calcium, magnesium, vitamin D, and vitamin K due to fat malabsorption
•Hepatobiliary disease
•Reduced weight-bearing 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 (SD) below the expected value, and vertebral compression and other pathologic fractures are common [16].
●Screening – To monitor bone health, individuals with CF should have yearly determination of calcium, phosphorus, intact parathyroid hormone, and 25-hydroxyvitamin D levels (table 2) [15]. 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 <10th percentile for age, forced expiratory volume in one second [FEV1] <50 percent predicted, glucocorticoid use of ≥5 mg daily for ≥90 days/year, delayed puberty, or a history of fractures). Even when no risk factors are present, patients 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 patients [20]. (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 [15].
•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, weight-bearing exercise is encouraged. Patients receive 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 status 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 individuals with CF 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). Weight-bearing 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 'Vitamin D' below and 'Vitamin K' below.)
Some groups have suggested that bisphosphonate treatment should be given to adult CF patients with markedly decreased bone mineral density (DXA Z-score <-2) [15]. In a systematic review that included 272 adult subjects, oral and intravenous bisphosphonate treatment improved bone mineral density by approximately 5 percent at several sites after 12 months of therapy [21]. The analysis did not detect a significant difference 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 anti-reabsorptive 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, have extremely long half-lives, and the long-term risks and benefits have not been fully explored [22]. For these reasons, we do not use bisphosphonates for children or adolescents.
Cystic fibrosis-related diabetes mellitus — CFRD is a common cause of nutritional decline in individuals with CF 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 with CF and almost 50 percent of adults over age 30 years. Patients with CF should be screened for CFRD using periodic oral glucose tolerance testing starting at 10 years of age. (See "Cystic fibrosis-related diabetes mellitus".)
Pulmonary function testing — There is a close correlation between pulmonary function test (PFT) results and nutritional status in patients with CF (figure 3A-B). 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) [23-25]. 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 a symptom of developing CFRD. (See 'Cystic fibrosis-related diabetes mellitus' above.)
Cystic fibrosis-related liver disease — CFLD is a common and important complication of CF, occasionally leading to cirrhosis and portal hypertension, and very rarely to liver failure. Approximately 20 to 40 percent of individuals with CF develop clinically detectable CFLD. Most of this CFLD does not progress to severe disease, but in the subset in which it does, it may progress rapidly. Patients with CFLD often have fat malabsorption because of insufficient or abnormal bile acids in the intestinal lumen, in addition to the underlying pancreatic insufficiency. Therefore, patients with CFLD 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 — Individuals with CF may be susceptible to small intestine bacterial overgrowth (SIBO), primarily because of decreased intestinal motility. The disorder can contribute to malnutrition by decreasing appetite and by interfering with fat absorption. SIBO should be considered in patients with suggestive clinical symptoms and/or deterioration in nutritional status. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Small intestine bacterial overgrowth'.)
Pancreatitis — Pancreatitis develops in approximately 10 percent of CF patients with pancreatic sufficiency and is rare among those with pancreatic insufficiency. Pancreatitis in CF patients 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, and compatible imaging findings. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Pancreatitis'.)
Intestinal resection — Approximately 10 percent of patients with CF 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 the terminal 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 DEFICITS AND GOALS
Calories — A wide range of energy requirements are reported in individuals with CF, ranging from normal to 150 percent of normal, depending on the CF genotype, the patient's age, and current state of health, including pulmonary function and the presence of CF-related liver disease (CFLD). In the past, the caloric requirement of a CF patient was estimated to be 130 percent of recommended dietary allowance for calories [26]. 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 [27-29].
Each patient should have a nutritional regimen tailored to his or her needs [30]. In clinical practice, 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 (>50 to 85th percentile for age) and BMI and height are steadily increasing along a percentile curve, energy intake is likely sufficient (see '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' below). In addition, the child should be evaluated for possible causes of growth failure, including insufficient pancreatic enzyme replacement therapy, gastrointestinal dysfunction, worsening pulmonary infection, or development of CF-related diabetes (CFRD). (See 'Evaluation for comorbidities' above.)
Measurement of resting energy expenditure (indirect calorimetry) is not practical for clinical management. The technique requires either endotracheal intubation or a tight-fitting hood to collect expired gases. CF patients do not tolerate either method well.
Fat-soluble vitamins — CFLD and pancreatic dysfunction lead to fat malabsorption, which predisposes patients to deficiencies of the fat-soluble vitamins: A, D, E, and K [31].
The CF Foundation (CFF) recommends supplementation of these vitamins for all children with CF (table 5 and table 4) [13]. 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.
Vitamin A — Because vitamin A is fat-soluble and requires bile acids for absorption, patients with CF 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).
Several reports show that vitamin A may reach toxic levels in some CF patients taking supplements [32,33]. This is particularly concerning because long-term vitamin A toxicity results in bone mineral loss and liver abnormalities. Many of the supplements used for patients with CF provide total doses of vitamin A that are well in excess of the CFF recommended intake. However, in some supplements, part of the vitamin A is provided in the form of beta-carotene. Beta-carotene is a provitamin A, and because its conversion to vitamin A is physiologically regulated, it has a lower risk for toxicity than preformed vitamin A [31].
●Monitoring – The CFF recommends measurement of serum retinol annually in all patients with CF (table 2), and that serum retinol binding protein and retinyl esters also be measured in those with liver disease [2,31,34]. However, serum retinol is a better marker of deficiency than excess. The optimal forms and dosing of vitamin A supplements and approach to monitoring is a subject of active study.
Vitamin D — Vitamin D deficiency is common among patients with CF and is probably a major contributor to bone disease [14,15]. (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 4). 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 patients with CF than vitamin D2 (ergocalciferol) [35]. 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 [36]. 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 individuals with CF take vitamin D supplements: recommended doses are 400 to 500 international units daily for patients younger than one year and 800 to 1000 international units daily for those 1 to 10 years of age. For those 10 years and older, the recommended daily intake is 800 to 2000 international units (table 4) [35].
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 [25-OH vitamin D levels] <30 ng/mL) [37]. 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 patients. Similarly, a report from three Canadian CF centers documented that 95 percent of CF patients had suboptimal vitamin D status despite having daily vitamin D intake above 400 international units [14]. Strategies for repletion of vitamin D are discussed separately. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)
●Monitoring – Vitamin D status should be assessed annually in all patients with CF by measuring serum 25-hydroxyvitamin D, preferably at the end of winter (table 2) [2,15]. 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) [15,35,37]. However, whether achieving 25-OH vitamin 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 deficiency of this vitamin 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 [38]. (See "Overview of vitamin E".)
●Recommended intake – The CFF recommends intake of vitamin E (as alpha-tocopherol) as shown in the following table (table 5) [2].
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) [39].
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 patients with CF [39]. 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 patients with CF (table 2) [2]. Serum vitamin E levels are strongly influenced by the concentration of serum lipids, do not accurately reflect tissue vitamin levels, and patients with CF typically have lower serum cholesterol levels than the reference population. Therefore, 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 patients with CF. Several reports demonstrate a direct correlation between vitamin K status and measures of bone health [31,40-42]. (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. Patients with CF 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 patients with 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 [2]. Adults should be supplemented with 2.5 to 5 mg weekly, and additional supplementation may be necessary during antibiotic therapy (table 5) [34]. 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 patients 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 CF patients even if there is no known liver disease or bleeding diathesis because patients may have CFLD for some time before it becomes clinically apparent.
PIVKA-II is more sensitive than prothrombin time in detecting vitamin K deficiency. Using this measure, 40 percent of patients with CF were found to have suboptimal vitamin K status, despite meeting the goals for vitamin K intake recommended by the CFF [43].
Essential fatty acids — Individuals with CF 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 at-risk patients; routine supplementation is not recommended, because clinical benefits have not been demonstrated [44,45].
●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 (DHA). 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 [46].
●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 patients with CF, 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 [46,47]. EFA deficiency is more common among infants and patients with pancreatic insufficiency.
●Monitoring – Routine EFA monitoring is not recommended for patients with CF [2,13]. However, patients at high risk for EFA deficiency, such as infants with growth failure or other suggestive symptoms or malnourished patients, should be monitored periodically (table 2) [48].
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 DHA 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 [48,49].
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 [50].
●Supplementation – For all CF patients, diets rich in EFA, including cold-water fish and vegetable oils (eg, flax, canola, or soy), are encouraged [2].
Routine supplementation with EFAs is not recommended, because clinical benefits have not been demonstrated [44,45]. 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 [44]. 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 patients with CF.
Supplementation and dietary modification are required for patients with documented EFA deficiency.
Sodium — Individuals with CF are prone to hyponatremic dehydration under conditions of heat stress, especially with exercise. This was described in five patients during a summer heat wave in 1948 who developed heat exhaustion with low serum sodium [51]. The risk for hyponatremic dehydration is increased during infancy and in hot climates [52]. A similar picture can develop in infants without heat stress [53]. To avoid these potentially life-threatening complications, routine supplementation with sodium chloride is recommended, depending upon the patient's age and climate conditions (table 6) [13].
Fluoride — Infants and children with CF require fluoride for dental health at the same levels as healthy children [13]. 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 CF foundation suggests an empiric trial of zinc supplementation (1 mg elemental zinc/kg/day in divided doses for six months) [2]. 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
Oral — All individuals with CF should be given dietary advice to encourage a balanced diet with adequate energy intake to target growth between the 50th and 85th body mass index (BMI) percentile for age. Caloric goals will often be higher than those for the general population. Pancreatic enzyme replacement therapy should be provided for those with pancreatic insufficiency. (See 'Growth' above and 'Calories' above and "Cystic fibrosis: Assessment and management of pancreatic insufficiency".)
For infants with CF, human milk feeding is specifically encouraged [13]. 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 milk 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'.)
Parents and caregivers should be educated to use behavioral techniques to promote positive feeding behaviors [13]. 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
For patients with suboptimal growth, the initial intervention is to provide more intensive dietary advice to increase caloric intake [10,13]. A number of studies support this approach and show nutritional benefit through counseling with the use of behavior modification strategies to support dietary change [54-58]. 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 [59,60]. The behavioral techniques included differential attention (parents praised children for desired eating behaviors and ignored non-eating 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 [61,62]. 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 patients receiving nutritional education alone.
In addition to nutritional and behavioral counseling, patients 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".)
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 suggests a trial of zinc supplementation. (See 'Zinc' above.)
If dietary counseling is not successful, a liquid supplement that is high in calories and protein can be added to the diet [10]. A variety of supplements are available and are appropriate for use by patients with CF (table 7). 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 [63], and patients often 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 CF patients who have moderate malnutrition [64].
Pharmacologic options
●Growth hormone – A few clinical trials have examined the use of recombinant growth hormone in children with CF and growth failure, with 12 months follow-up [65,66]. These have shown modest improvement in height, weight, lean tissue mass compared with no treatment, and a very small improvement in forced vital capacity (FVC), but not other measures of pulmonary function [67]. No adverse effects on blood glucose were noted. Current data are insufficient to justify routine use of growth hormone in this population outside of a clinical study.
●Appetite stimulants – 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) [68]. There have been concerns about the efficacy, the 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 [69-71]. 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 [72].
●Insulin – In patients 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 patients with progressively worsening nutritional status. (See "Cystic fibrosis-related diabetes mellitus", section on 'Indications'.)
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 [9,10,73]. Aspects of enteral nutrition that are specific to patients with CF are outlined here. An overview of enteral nutrition in children is presented separately. (See "Overview of enteral nutrition in infants and children".)
Enteral nutrition is widely used for patients with CF and perceived as helpful [74-76]. This practice is supported by a number of observational studies that suggest improved nutritional status and stabilization of lung function in CF patients receiving enteral nutrition, as illustrated by the following examples [75,77,78]:
●A series of 14 patients with moderate to severe lung disease were compared with age- and disease-matched contemporary controls, with a mean follow-up of 1.1 years [79]. The patients receiving enteral nutrition experienced a weight percentile increase, while growth percentiles declined in the comparison group. The forced expiratory volume in one second (FEV1) in the enteral nutrition group did not change, while the FEV1 of the comparison group worsened.
●A series of 53 patients with CF, 10 of whom were children, showed an increase in expected weight and stabilization of lung function, but these outcomes were not compared with a control group [75].
No randomized studies of enteral nutrition have been performed in patients with CF. Therefore, the clinical benefits and potential adverse consequences, including effects on quality of life, have not been rigorously addressed [78].
Route — Enteral nutrition is usually provided to patients with CF via gastrostomy tube (G-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 patients.
G-tubes can be placed surgically, endoscopically, or by an interventional radiologist, with minimal risk. If general anesthesia is not advisable for a particular patient, the procedure can be performed under sedation and local anesthesia. A skin-level device (or "button") can be used so that the patient can disconnect from all tubing between feeds, to optimize mobility and cosmesis.
Schedule — Schedules for tube feeding vary and should take into account the patient's activities and other therapies. Feeds can be instilled continuously, as boluses, or 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 patient 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.
CF patients 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 semi-elemental (table 8). The protein in a semi-elemental 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, a non-elemental formula plus pancreatic enzyme replacement was as well-absorbed as a semi-elemental formula without pancreatic enzymes [80].
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, in established diabetics, 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 listed in the table (table 8).
Enzyme replacement — There is little evidence to determine the best way to administer pancreatic enzyme replacement therapy in conjunction with enteral nutrition. In the absence of evidence-based guidelines, 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, as outlined in the table (table 8).
●Supply 1600 to 2000 lipase units per gram LCT (table 9). See pancrelipase drug information.
•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 five years of age and older. Efficacy data are still limited, but a small trial suggests that it can help reduce early morning satiety and bloating for some individuals [81]. 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 [82]. 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'.)
Parenteral nutrition — Parenteral nutrition (PN) should be prescribed for CF patients 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 patients with CF but was also associated with higher rates of sepsis [83]. Moreover, after PN was discontinued, weight decreased again, and no long-term gain was achieved. PN should not be a part of palliative care.
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 5th to 6th 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 10th to 12th 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 e-mail 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 – Nutritional issues in cystic fibrosis (CF) are pervasive and are not fully explained by pancreatic insufficiency or overcome by pancreatic enzyme replacement therapy. Early recognition and intensive treatment of undernutrition in patients with CF can minimize the damaging effects of malnutrition on lung disease, longevity, and quality of life. (See 'Introduction' above.)
●Causes of nutritional problems in CF
•Pancreatic insufficiency – Pancreatic insufficiency is an important contributor to malnutrition in most individuals with CF. The main consequences are due to fat malabsorption, which contributes to growth failure, fat-soluble vitamin deficiencies, and bone disease. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency".)
•CF-related diabetes (CFRD) – CFRD is an important cause of nutritional decline and affects approximately 15 percent of adolescents with CF and almost 50 percent of adults over age 30. Annual screening for CFRD is recommended beginning at age 10 years, carried out at a time of clinical stability. (See 'Cystic fibrosis-related diabetes mellitus' above and "Cystic fibrosis-related diabetes mellitus".)
•Other – Bile salt abnormalities and small bowel bacterial overgrowth also compromise nutrient absorption, while inflammatory lung disease increases energy needs.
●Routine monitoring – All patients with CF should have regular nutritional assessments at three-monthly intervals for early detection of nutritional deterioration (table 1). (See 'Assessing and monitoring nutrition' above.)
•Anthropometric measurements are tracked against standard curves. For children with CF, the target range for body mass index (BMI) is above the 50th percentile (figure 2). For adults, the target is a BMI at or above 22 kg/m2 for females and 23 kg/m2 for males. (See 'Growth' above.)
•Laboratory tests are performed to monitor for specific deficiencies (table 2). (See 'Blood tests' above.)
●Management of nutritional comorbidities
•Bone health– Bone disease is common in patients with CF and progresses with age. All individuals with CF 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 – We recommend that all individuals with CF take supplements to meet disease-specific recommended intakes for fat-soluble vitamins (table 5 and table 4) (Grade 1B). Several different commercially available vitamin supplements provide doses within the target range. Vitamin sufficiency should be assessed with annual laboratory monitoring (table 2). (See 'Fat-soluble vitamins' above.)
•Sodium requirements – Because of sodium losses in sweat, individuals with CF are prone to hyponatremic dehydration under conditions of heat stress. Most patients will need supplementation of sodium chloride to compensate for estimated sodium losses, which depend on the patient's age and climate conditions (table 6). (See 'Sodium' above.)
●Diet and nutrition support – All individuals with CF should be given dietary counseling to encourage a balanced diet with adequate calories to ensure good growth. Caloric goals will often be higher than for the general population. Patients 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' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Chris Coburn-Miller, MSRD, CSP, who contributed to an earlier version of this topic review.
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